Heteroaromatic glucokinase activators

ABSTRACT

2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 3-position being a substituted phenyl group and at the 2-position being a methyl cycloalkyl ring, said propionamides being glucokinase activators which increase insulin secretion in the treatment of type II diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of application Ser. No.09/675,781, filed on Sep. 28, 2000, now allowed, which is a CIP of U.S.Ser. No. 09/526,143 filed on Mar. 15, 2000, now U.S. Pat. No. 6,320,050,which claims benefit of U.S. Provisional Application No. 60/126,707filed Mar. 29, 1999, and claims benefit of U.S. Provisional ApplicationNo. 60/165,944 filed Nov. 17, 1999.

BACKGROUND OF THE INVENTION

[0002] Glucokinase (GK) is one of four hexokinases that are found inmammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.)Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinasescatalyze the first step in the metabolism of glucose, i.e., theconversion of glucose to glucose-6-phosphate. Glucokinase has a limitedcellular distribution, being found principally in pancreatic β-cells andliver parenchymal cells. In addition, GK is a rate-controlling enzymefor glucose metabolism in these two cell types that are known to playcritical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly,K. L., and Ruderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C.Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994].The concentration of glucose at which GK demonstrates half-maximalactivity is approximately 8 mM. The other three hexokinases aresaturated with glucose at much lower concentrations (<1 mM). Therefore,the flux of glucose through the GK pathway rises as the concentration ofglucose in the blood increases from fasting (5 mM) to postprandial(≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R.G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13(R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review,Inc., Palo Alto, Calif., pages 463-496, 1993]. These findingscontributed over a decade ago to the hypothesis that GK functions as aglucose sensor in β-cells and hepatocytes (Meglasson, M. D. andMatschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recentyears, studies in transgenic animals have confirmed that GK does indeedplay a critical role in whole-body glucose homeostasis. Animals that donot express GK die within days of birth with severe diabetes whileanimals overexpressing GK have improved glucose tolerance (Grupe, A.,Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu,E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase inglucose exposure is coupled through GK in β-cells to increased insulinsecretion and in hepatocytes to increased glycogen deposition andperhaps decreased glucose production.

[0003] The finding that type II maturity-onset diabetes of the young(MODY-2) is caused by loss of function mutations in the GK gene suggeststhat GK also functions as a glucose sensor in humans (Liang, Y.,Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995).Additional evidence supporting an important role for GK in theregulation of glucose metabolism in humans was provided by theidentification of patients that express a mutant form of GK withincreased enzymatic activity. These patients exhibit a fastinghypoglycemia associated with an inappropriately elevated level of plasmainsulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med.338, 226-230, 1998). While mutations of the GK gene are not found in themajority of patients with type II diabetes, compounds that activate GKand, thereby, increase the sensitivity of the GK sensor system willstill be useful in the treatment of the hyperglycemia characteristic ofall type II diabetes. Glucokinase activators will increase the flux ofglucose metabolism in β-cells and hepatocytes, which will be coupled toincreased insulin secretion. Such agents would be useful for treatingtype II diabetes.

SUMMARY OF THE INVENTION

[0004] This invention provides a compound, comprising an amide of theformula:

[0005] wherein R¹ and R² are independently hydrogen, halo, amino,hydroxyamino, cyano, nitro, lower alkyl, —OR⁵, —C(O)OR⁶, perfluoro-loweralkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkylsulfonyl, lower alkoxy lower alkyl sulfonyl, perfluoro-lower alkylsulfonyl, lower alkyl sulfinyl, or sulfonamido; R³ is cycloalkyl havingfrom 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms;

[0006] R⁴ is an unsubstituted or mono-substituted five- or six-memberedheteroaromatic ring connected by a ring carbon atom to the amine groupshown, which five- or six-membered heteroaromatic ring contains from 1to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with oneheteroatom being nitrogen which is adjacent to the connecting ringcarbon atom; said mono-substituted heteroaromatic ring beingmonosubstituted at a position on a ring carbon atom other than adjacentto said connecting carbon atom with a substituent selected from thegroup consisting of lower alkyl, halo, nitro, cyano, perfluoro-loweralkyl; oxo, —(CH₂)_(n)—OR⁷, —(CH₂)_(n)—C(O)—OR⁷, —(CH₂)_(n)—C(O)—NH—R⁷,—C(O)C(O)—OR⁷, or —(CH₂)_(n)—NHR⁷; n is 0, 1, 2, 3 or 4; R⁵ is hydrogen,lower alkyl, or perfluoro-lower alkyl; R⁶ is lower alkyl; and R⁷ ishydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.

[0007] The compounds of formula I have been found to activateglucokinase in vitro. Glucokinase activators are useful for increasinginsulin secretion in the treatment of type II diabetes.

DETAILED DESCRIPTION OF THE INVENTION

[0008] This invention provides a compound, comprising an amide of theformula:

[0009] wherein R¹ and R² are independently hydrogen, halo, amino,hydroxyamino, cyano, nitro, lower alkyl, —OR⁵, —C(O)OR⁶, perfluoro-loweralkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkylsulfinyl, lower alkyl sulfonyl ring , lower alkoxy lower alkyl sulfonyl,perfluoro-lower alkyl sulfonyl, or sulfonamido; R³ is preferablycycloalkyl having from 3 to 7 carbon atoms atoms but also includes loweralkyl having from 2 to 4 carbon atoms, R⁴ is an unsubstituted ormono-substituted five or six -membered heteroaromatic connected by aring carbon atom to the amine group shown, which five- or six-memberedheteroaromatic ring contains from 1 to 3 heteroatoms selected fromsulfur, oxygen or nitrogen, with one heteroatom being nitrogen which isadjacent to the connecting ring carbon atom; said mono-substitutedheteroaromatic ring being monosubstituted at a position on a ring carbonatom other than adjacent to said connecting carbon atom with asubstituent selected from the group consisting of lower alkyl, halo,nitro, cyano, perfluoro-lower alkyl; oxo, —(CH₂)_(n)—OR⁷,—(CH₂)_(n)—C(O)—OR⁷, —(CH₂)_(n)—C(O)—NH—R⁷, —C(O)C(O)—OR⁷, or—(CH₂)_(n)—NHR⁷; n is 0, 1, 2, 3 or 4; R⁵ is hydrogen, lower alkyl, orperfluoro-lower alkyl; R⁶ is lower alkyl; and R⁷ is hydrogen or loweralkyl; or a pharmaceutically acceptable salt thereof.

[0010] In the compound of formula I, the “.” illustrates the asymmetriccarbon atom in this compound. The compound of formula I may be presenteither as a racemate or in the “R” configuration at the asymmetriccarbon shown. The “R” enantiomers are preferred.

[0011] As used throughout this application, the term “lower alkyl”includes both straight chain and branched chain alkyl groups having from1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl,preferably methyl and ethyl. As used herein, the term “halogen” is usedinterchangeably with the word “halo”, and, unless otherwise stated,designates all four halogens, i.e. fluorine, chlorine, bromine, andiodine. As used herein, “perfluoro-lower alkyl” means any lower alkylgroup wherein all of the hydrogens of the lower alkyl group aresubstituted or replaced by fluoro. Among the preferred perfluoro-loweralkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl,etc.

[0012] As used herein, the term “lower alkoxy” signifies a lower alkylgroup as defined above linked via an oxygen to the remainder of themolecule and includes both straight chain and branched chain alkoxygroups having from 1 to 7 carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, preferably methoxy and ethoxy. “Lower alkoxy loweralkyl” signifies a lower alkoxy linked via an oxygen to a lower alkylgroup, which is linked to the remainder of the molecule.

[0013] As used herein the term “aryl” signifies aryl mononucleararomatic hydrocarbon groups such as phenyl, tolyl, etc. which can beunsubstituted or substituted in one or more positions with halogen,nitro, lower alkyl, or lower alkoxy substituents and polynuclear arylgroups, such as naphthyl, anthryl, and phenanthryl, which can beunsubstituted or substituted with one or more of the aforementionedgroups. Preferred aryl groups are the substituted and unsubstitutedmononuclear aryl groups, particularly phenyl. The term “arylalkyl”denotes an alkyl group, preferably lower alkyl, in which one of thehydrogen atoms can be replaced by an aryl group. Examples of arylalkylgroups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl,4-methoxybenzyl and the like.

[0014] As used herein, the term “lower alkanoic acid” denotes loweralkanoic acids containing from 2 to 7 carbon atoms such as propionicacid, acetic acid and the like. The term “lower alkanoyl” denotesmonovalent alkanoyl groups having from 2 to 7 carbon atoms such aspropionyl, acetyl and the like. The term “aroic acids” denotes arylalkanoic acids where aryl is as defined above and alkanoic contains from1 to 6 carbon atoms. The term “aroyl” denotes aroic acids wherein arylis as defined hereinbefore, with the hydroxide group of the COOH moietyremoved. Among the preferred aroyl groups is benzoyl.

[0015] As used herein, —C(O)OR⁶ represents

[0016] and so forth.

[0017] The heteroaromatic ring defined by R⁴ can be an unsubstituted ormono-substituted five- or six-membered heteroaromatic ring having from 1to 3 heteroatoms selected from the group consisting of oxygen, nitrogen,or sulfur and connected by a ring carbon to the amine of the amide groupshown. The heteroaromatic ring contains a first nitrogen heteroatomadjacent to the connecting ring carbon atom and if present, the otherheteroatoms can be sulfur, oxygen or nitrogen. Such heteroaromatic ringsinclude, for example, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl,and pyrazolyl. Among the preferred heteroaromatic rings are includedpyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl.These heteroaromatic rings which constitute R⁴ are connected via a ringcarbon atom to the amide group to form the amides of formula I. The ringcarbon atom of the heteroaromatic ring which is connected via the amidelinkage to form the compound of formula I cannot contain anysubstituent.

[0018] When R⁴ is an unsubstituted or mono-substituted five-memberedheteroaromatic ring, the preferred rings are those which contain anitrogen heteroatom adjacent to the connecting ring carbon and a secondheteroatom adjacent to the connecting ring carbon.

[0019] The preferred five-membered heteroaromatic rings contain 2 or 3heteroatom with thiazolyl, imidazolyl, oxazolyl and thiadiazolyl beingespecially present. When the heteroaromatic ring is a six-memberedheteroaromatic ring, the ring is connected by a ring carbon to the aminegroup shown, with one nitrogen heteroatom being adjacent to theconnecting ring carbon atom. The preferred six-membered heteroaromaticrings include, for example, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and triazinyl.

[0020] The term “pharmaceutically acceptable salts” as used hereininclude any salt with both inorganic or organic pharmaceuticallyacceptable acids such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid,para-toluene sulfonic acid and the like. The term “pharmaceuticallyacceptable salts” also includes any pharmaceutically acceptable basesalt such as amine salts, trialkyl amine salts and the like. Such saltscan be formed quite readily by those skilled in the art using standardtechniques.

[0021] During the course of the reactions provided below in the ReactionScheme and discussion, the various functional groups such as the freecarboxylic acid or hydroxy groups may be protected via conventionalhydrolyzable ester or ether protecting groups. As used herein, the term“hydrolyzable ester or ether protecting groups” designates any ester orether conventionally used for protecting carboxylic acids or alcoholswhich can be hydrolyzed to yield the respective carboxyl or hydroxylgroup. Exemplary ester groups useful for those purposes are those inwhich the acyl moieties are derived from a lower alkanoic, aryl loweralkanoic, or lower alkane dicarboxylic acid. Among the activated acidswhich can be utilized to form such groups are acid anhydrides, acidhalides, preferably acid chlorides or acid bromides derived from aryl orlower alkanoic acids. Examples of anhydrides are anhydrides derived frommonocarboxylic acid such as acetic anhydride, benzoic acid anhydride,and lower alkane dicarboxylic acid anhydrides, e.g. succinic anhydrideas well as chloro formates e.g. trichloro, ethylchloro formate beingpreferred. A suitable ether protecting group for alcohols are, forexample, the tetrahydropyranyl ethers such as4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are aroylmethyletherssuch as benzyl, benzhydryl or trityl ethers or α-lower alkoxy loweralkyl ethers, for example, methoxymethyl or allylic ethers or alkylsilylethers such as trimethylsilylether.

[0022] Similarly, the term “amino protecting group” designates anyconventional amino protecting group which can be cleaved to yield thefree amino group. The preferred protecting groups are the conventionalamino protecting groups utilized in peptide synthesis. Especiallypreferred are those amino protecting groups which are cleavable undermildly acidic conditions from about pH 2 to 3.

[0023] Particularly preferred amino protecting groups are t-butylcarbamate (BOC), benzyl carbamate (CBZ), and 9-fluorenylmethyl carbamate(FMOC).

[0024] In accordance with one embodiment of this invention, R³ iscyclopentyl (the compound I-D). The embodiments of the compound I-D arethose compounds where R⁴ is an unsubstituted thiazole (Compound I-D1).Among the various embodiments of the compound of I-D 1 are includedthose compounds where:

[0025] (a) one of R¹ and R² is hydrogen, halo, perfluoro-lower alkyl andthe other of said R¹ and R² is halo, nitro, or perfluoro-lower alkyl;

[0026] (b) one of R¹ and R² is amino, halo, nitro or hydrogen and theother of said R¹ and R² is amino, cyano or nitro;

[0027] (c) one of R¹ and R² is lower alkylthio, perfluoro-lower alkylthio, halo or hydrogen and the other of said R¹ and R² isperfluoro-lower alkylthio, lower alkylsulfinyl or lower alkylthio;

[0028] (d) one of R¹ and R² is lower alkyl sulfonyl, hydrogen, nitro,cyano, amino, hydroxyamino, sulfonamido or halo, and the other of saidR¹ and R² is lower alkyl sulfonyl;

[0029] (e) one of R¹ and R² is lower alkyl sulfonyl, and the other ofsaid R¹ and R² is halo or perfluoro-lower alkyl;

[0030] (f) one of R¹ and R² is perfluoro-lower alkyl sulfonyl orhydrogen and the other of said R¹ and R² is perfluoro-lower alkylsulfonyl;

[0031] (g) one of R¹ and R² is —OR⁵, or —C(O)—OR⁶ and the other of saidR¹ and R² is hydrogen or —OR⁵; and R⁵ and R⁶ are as above

[0032] (h) one of R¹ and R² is —OR⁵ and the other is halo, and

[0033] (i) one of R¹ and R² is hydrogen (preferably R¹) and the other ofsaid R¹ and R² is lower alkoxy lower alkyl sulfonyl (preferably R²).

[0034] In accordance with another embodiment of this invention where R³is cyclopentyl, the embodiments are those compounds where R⁴ is amono-substituted thiazole (compounds I-D2). Among the embodiments ofcompounds I-D2, are those compounds where the mono-substitution is—(CH₂)_(n)—OR⁷ and n and R⁷ are as above (compounds I-D2(a)). Among theembodiments of compounds I-D2 (a) are those compounds where:

[0035] a) one of R¹ and R² is halo and the other of said R¹ and R² ishydrogen or halo;

[0036] b) one of R¹ and R² is lower alkyl sulfonyl, and the other ofsaid R¹ and R² is lower alkyl sulfonyl or hydrogen; and

[0037] c) one of R¹ and R² is hydrogen and the other of said R¹ and R²is lower alkyl or perfluoro-lower alkyl.

[0038] In accordance with another embodiment of the invention where R³is cyclopentyl and R⁴ is a mono-substituted thiazole (Compounds I-D2),are those compounds where the mono-substitution is lower alkyl. Amongthe embodiments of these compounds are compounds where:

[0039] a) one of R¹ and R² is hydrogen or halo and the other of R¹ andR² is halo;

[0040] b) one of R¹ and R² is lower alkyl sulfonyl and the other of R¹and R² is hydrogen or halo.

[0041] Among another embodiment of the compounds I-D are those compoundswhere the mono-substituted thiazole is substituted with—(CH₂)_(n)—C(O)—OR⁷ wherein n is 0 or 1 and R⁷ is hydrogen, or loweralkyl (Compounds I-D2(c)). Among the embodiments of compounds of formulaI-D2(c) are those compounds where:

[0042] a) one of R¹ and R² is hydrogen and the other of said R¹ and R²is halo;

[0043] b) R¹ and R² are each independently halo;

[0044] c) one of R¹ and R² is halo and the other of said R¹ and R² isperfluoro-lower alkyl;

[0045] d) one of R¹ or R² is nitro, amino or hydrogen and the other ofsaid R¹ and R² is nitro or amino; and

[0046] e) one of R¹ and R² is lower alkyl sulfonyl, perfluoro-loweralkyl, halo or hydrogen and the other of said R¹ and R² is lower alkylsulfonyl;

[0047] f) one of of R¹ and R² is hydrogen, halo or perfluoro-lower alkyland the other of said R¹ and R² is perfluoro-lower alkyl sulfonyl.

[0048] In accordance with another embodiment of this invention, where R³and cyclopentyl and R⁴ is a mono-substituted thiazole (Compounds I-D2)are those compounds where the mono-substituted thiazole is substitutedwith —C(O)—C(O)—OR⁷ wherein R⁷ is as above (Compounds I-D2(d)).

[0049] Among the embodiments of compound I-D2(d) are those compoundswhere:

[0050] a) one of R¹ and R² are hydrogen and the other of said R¹ and R²is nitro or amino;

[0051] b) one of R¹ and R² is halo or perfluoro-lower alkyl and theother of said R¹ and R² is perfluoro-lower alkyl, halo or hydrogen; and

[0052] c) one of R¹ and R² is hydrogen or halo and the other of said R¹and R² is lower alkyl sulfonyl.

[0053] In accordance with another embodiment of this invention, where R³is cyclopentyl and R⁴ is a mono-substituted thiazole, compounds I-D2,are those compounds where the mono-substitution on the thiazole ring isa nitro group and one of R¹ and R² are hydrogen and halo and the otherof R¹ and R² is halo or lower alkyl sulfonyl, or R¹ and R² are eachindependently halo (compound of formula I-D2(e)).

[0054] In accordance with another embodiment of this invention, where R³is cyclopentyl and R⁴ is a mono-substituted thiazole, compounds I-D2,are those compounds where the mono-substitution on the thiazole ring is—(CH₂)_(n)—C(O)—NH—R⁷ where n and R⁷ are as in formula I, preferablywhere one of R¹ and R² is lower alkyl sulfonyl or halo and the other ofR¹ and R² is halo or hydrogen.

[0055] In accordance with another embodiment of this invention, where R³is cyclopentyl and R⁴ is a mono-substituted thiazole, compounds I-D2,are those compounds where the mono-substitution on the thiazole ring ishalo, preferably where one of R¹ and R² is hydrogen or halo and theother of R¹ and R² is lower alkyl sulfonyl.

[0056] In accordance with another embodiment of this invention, where R³is cyclopentyl (Compound I-D) and R⁴is an unsubstituted pyridine(Compounds I-D3). Among the embodiments of compound I-D3 are thosecompounds where:

[0057] a) one of R¹ and R² is halo and the other of R¹ and R² is loweralkyl sulfonyl;

[0058] b) one of R¹ and R² are halo, perfluoro-lower alkyl or hydrogenand the other of said R¹ and R² is halo, perfluoro-lower alkyl, amino,cyano or nitro;

[0059] c) one of R¹ and R² is lower alkyl thio, perfluoro-lower alkylthio or cyano, and the other is hydrogen;

[0060] d) one of R¹ and R² is lower alkyl sulfonyl, halo, cyano, nitroor hydrogen and the other of said R¹ and R² is lower alkyl sulfonyl, and

[0061] e) one of R¹ and R² is perfluoro-lower alkyl sulfonyl, loweralkyl sulfonyl or hydrogen and the other of said R¹ and R² isperfluoro-lower alkyl sulfonyl, or perfluoro-lower alkyl.

[0062] In accordance with another embodiment of the invention, where R³is cyclopentyl (Compounds I-D) are those compounds where R⁴ is amono-substituted pyridine ring. Among the embodiments of themono-substituted pyridine (Compounds I-D4) are those compounds where themono-substitution is cyano. Among the embodiments of such compounds arethose compounds where one of R¹ and R² is perfluoro-lower alkyl or haloand the other of R¹ and R² is lower alkyl thio or halo, especially whereR¹ and R² are each independently halo.

[0063] In accordance with another embodiment of the invention, where R³is cyclopentyl (Compounds I-D) are those compounds where R⁴ is amono-substituted pyridine ring. Among the embodiments of themono-substituted pyridine (Compounds I-D4) are those compounds where themono-substitution is —(CH₂)_(n)—C(O)—OR⁷ wherein n and R⁷ are as above(compound I-D4(a)). Among the embodiments of compounds I-D4(a) are thosecompounds where:

[0064] a) R¹ and R² are each independently halo;

[0065] b) one of R¹ and R² is halo or hydrogen and the other of said R¹and R² is halo, amino, cyano, nitro or perfluoro-lower alkyl; and

[0066] c) one of R¹ and R² is perfluoro-lower alkyl sulfonyl, loweralkyl sulfonyl or hydrogen and the other of said R¹ and R² isperfluoro-lower alkyl sulfonyl or lower alkyl sulfonyl.

[0067] Other embodiments of the compounds of formula I-D4 are thosecompounds where the pyridine ring is mono-substituted with—(CH₂)_(n)—OR⁷ wherein n and R⁷ are as above (Compounds I-D4(b)). Amongthe embodiments of the compound I-D4(b) are those compounds where:

[0068] a) one of R¹ and R² is halo and the other of said R¹ and R² ishydrogen or halo; and

[0069] b) one of R¹ and R² is lower alkyl sulfonyl or hydrogen and theother of said R¹ and R² is lower alkyl sulfonyl.

[0070] Another embodiment of compounds where R³ is cyclopentyl and R⁴ isa mono-substituted pyridine ring are those compounds where the pyridinering is mono-substituted with a halo or perfluoro lower alkylsubstituent, the compound of formula I-D4(c). Among the embodiments ofthe compound of formula I-D4(c) are those compounds where:

[0071] a) one of R¹ and R² is halo or perfluoro-lower alkyl and theother of said R¹ and R² is halo, nitro, lower alkyl suffonyl, or loweralkyl thio;

[0072] b) one of R¹ and R² is halo or hydrogen and the other of said R¹and R² is halo; and

[0073] c) one of R¹ and R² is halo, nitro or hydrogen and the other ofsaid R¹ and R² is perfluoro-lower alkyl sulfonyl or lower alkylsulfonyl.

[0074] In accordance with another embodiment of this invention arecompounds of where R³ is cyclopentyl and R⁴ is a mono-substitutedpyridine are those compounds where the pyridine is mono-substituted witha nitro substituent, (Compound I-D4(d)). The embodiments of the compoundI-D4(d) include compounds where one of R¹ and R² is halo and the otherof said R¹ or R² is hydrogen, halo, or lower alkyl sulfonyl andcompounds where one of R¹ and R² is halo or perfluoro-lower alkyl andthe other of said R¹ or R² is halo or lower alkyl thio.

[0075] In accordance with another embodiment of this invention arecompounds of formula I where R³ is cyclopentyl and R⁴ ismono-substituted pyridine and the mono-substitution is a lower alkylgroup (Compounds I-D4(e)). Among the embodiments of compounds I-D4(e)are those compounds where one of R¹ and R² is halo or hydrogen and theother of said R¹ and R² is halo, perfluoro-lower alkyl, perfluoro-loweralkyl sulfonyl, or lower alkyl sulfonyl, and compounds where one of R¹and R² is halo and other of said R¹ or R² is lower alkyl sulfonyl.

[0076] In accordance with another embodiment of this invention where R³is cyclopentyl and R⁴is a mono-substituted pyridine are those compoundswhere the mono-substituent is —(CH₂)_(n)—C(O)—NH—R⁷ wherein n and R⁷ areas above (Compound I-D4(f)). Among the embodiments of compound I-D4(f)are those compounds wherein one of R¹ and R² are independently selectedfrom the group consisting of halo or hydrogen and the other of said R¹and R² is halo, or lower alkyl sulfonyl, and those compounds where oneof R¹ and R² is halo and other of said R¹ or R² is perfluoro-loweralkyl.

[0077] Another embodiment of this invention where R³ is cyclopentyl arethose compounds where R⁴ is an unsubstituted imidazolyl (Compound I-D5).Among the embodiments of compounds I-D5 are those compounds wherein oneof R¹ and R² is selected from the group consisting of halo and hydrogenand the other of said R¹ and R² is halo, or lower alkyl sulfonyl andthose compounds where one of R¹ and R² is lower alkyl sulfonyl and otherof said R¹ or R² is nitro or perfluoro-lower alkyl.

[0078] Another embodiment of the compounds of this invention are thosecompounds where R³ is cyclopentyl and R⁴ is an isoxazolyl ring (thecompound I-D6). The embodiments of compound I-D6 are those compoundswhere the isoxazolyl ring is unsubstituted or substituted, preferablymono-substituted. Among the mono-substituted substituents, the preferredsubstituents substituted on the isoxazolyl ring is lower alkyl. Anembodiment of the compound I-D6, either where the isoxazolyl ring isunsubstituted or substituted with a lower alkyl substituent are thosecompounds where one of R¹ and R² is halo, nitro, perfluoro-lower alkyl,or lower alkyl sulfonyl and the other of R¹ and R² is hydrogen or halo.

[0079] Another embodiment of this invention where R³ is cyclopentyl arethose compounds where R⁴ is either an unsubstituted oxazolyl, or anoxazolyl mono-substituted with a lower alkyl group. Another embodimentwith respect to either of those compounds are those compounds where oneof R¹ or R² is halo, nitro or perfluoro-lower alkyl, or lower alkylsulfonyl and the other is of R¹ or R² is hydrogen or halo.

[0080] Another embodiment of this invention where R³ is cyclopentyl arethose compounds where R⁴ is pyridazinyl which is either unsubstituted orsubstituted with a lower alkyl group (Compound I-D7). Embodiments of thecompound I-D7 are encompassed by this invention include those compoundswhere one of R¹ or R² is halo, nitro or perfluoro-lower alkyl, or loweralkyl sulfonyl and the other of said R¹ or R² is hydrogen or halo.

[0081] Another embodiment of this invention where R³ is cyclopentylinclude compounds where R⁴ is unsubstituted pyrimidinyl. The embodimentsof those compounds where R³ is cyclopentyl and R⁴ is unsubstitutedpyrimidinyl include those compounds where one of R¹ or R² is halo,nitro, perfluoro-lower alkyl, or lower alkyl sulfonyl and the other ishydrogen or halo and those compounds where one of R¹ and R² is loweralkyl sulfonyl and other of said R¹ or R² is cyano, nitro, orperfluoro-lower alkyl.

[0082] In accordance with another embodiment of the invention, where R³is cyclopentyl (Compounds I-D) are those compounds where R⁴ is amono-substituted pyrimidine ring. Among the embodiments of themono-substituted pyrimidine are those compounds where themono-substitution is lower alkyl. Among the embodiments of suchcompounds are those compounds where:

[0083] a) one of R¹ and R² is perfluoro-lower alkyl and the other ofsaid R¹ and R² is hydrogen;

[0084] b) one of R¹ and R² is lower alkyl sulfonyl and the other of saidR¹ and R² is cyano or nitro; and

[0085] c) one of R¹ and R² is lower alkyl sulfonyl and the other of saidR¹ and R² is perfluoro-lower alkyl,

[0086] d) one of R¹ and R² is lower alkyl sulfonyl and the other of saidR¹ and R² is halo.

[0087] In accordance with yet another embodiment of the invention, whereR³ is cyclopentyl (Compounds I-D) are those compounds where R⁴ is amono-substituted dihydro pyrimidine ring. Among the embodiments of themono-substituted pyrimidine are those compounds where themono-substitution is oxo. Among the embodiments of such compounds arethose compounds where one of R¹ and R² is lower alkyl sulfonyl and theother of said R¹ and R² is halo, nitro, or perfluoro-lower alkyl.

[0088] Another embodiment of this invention includes compounds where R³is cyclopentyl where R⁴ is an unsubstituted thiadiazolyl ring. Among theembodiments included within those compounds where R³ is cyclopentyl andR⁴ is an unsubstituted thiadiazolyl ring are those compounds wherein oneof R¹ or R² is halo, nitro or perfluoro-lower alkyl, or lower alkylsulfonyl and the other of said R¹ and R² is hydrogen or halo.

[0089] In accordance with other embodiments of this invention, R³ in thecompound of formula I can be cycloheptyl or cyclohexyl. The embodimentsof the compound of formula I where R³ is cycloheptyl or cyclohexylinclude those compounds where R⁴ is thiazolyl which can bemono-substituted or unsubstituted.

[0090] Embodiments included within such compounds where R³ iscycloheptyl or cyclohexyl and R⁴ is an unsubstituted thiazolyl includethose compounds wherein one of R¹ and R² is halo, lower alkyl sulfonyl,perfluoro-lower alkyl sulfonyl, perfluoro-lower alkyl, and the other isof said R¹ and R² is halo, perfluoro-lower alkyl or hydrogen.

[0091] In accordance with another embodiment of this invention, R³ iscyclopentyl (Compound I-D) and R⁴ is an unsubstituted pyrazinyl. Amongthe embodiments of such compounds are those compounds where:

[0092] a) one of R¹ and R² is lower alkyl sulfonyl, halo, orperfluoro-lower alkyl and the other of R¹ and R² is hydrogen, halo,cyano, nitro, or perfluoro-lower alkyl;

[0093] b) one of R¹ and R² is perfluoro-lower alkyl or lower alkylsulfonyl and the other of said R¹ and R² is hydrogen, cyano or nitro;

[0094] c) one of R¹ and R² is lower alkyl sulfonyl and the other isperfluoro-lower alkyl or halo.

[0095] In accordance with yet another embodiment of the invention, whereR³ is cyclopentyl (Compounds I-D) are those compounds where R⁴ isunsubstituted triazinyl. Among the embodiments of such compounds arethose compounds where R¹ and R² are each independently halo.

[0096] The compound of formula I can be prepared starting from thecompound of formula V by the following Reaction Scheme:

[0097] wherein R¹, R², R³ and R⁴are as above and R¹⁵ is hydrogen orlower alkyl.

[0098] The carboxylic acids or their lower alkyl esters of formula Vwherein one of R¹ and R² is nitro, cyano, thiol, thiomethyl,methylsulfonyl, amino, chloro, bromo, or iodo and the other is hydrogenare commercially available. In cases where only the carboxylic acids areavailable, they can be converted to the corresponding esters of loweralkyl alcohols using any conventional esterification methods. All thereactions hereto forward are to be carried out on lower alkyl esters ofthe carboxylic acids of formula V, or may be carried out on thecarboxylic acids themselves. The amino substituted compounds of formulaV can be converted to other substituents either before or afterconversion to the compounds of formula 1-a′. In this respect, the aminogroups can be diazotized to yield the corresponding diazonium compound,which in situ can be reacted with the desired lower alkyl thiol,perfluoro-lower alkyl thiol (see for example, Baleja, J. D. Synth. Comm.1984, 14, 215; Giam, C. S.; Kikukawa, K., J. Chem. Soc, Chem. Comm.1980, 756; Kau, D.; Krushniski, J. H.; Robertson, D. W, J. LabelledCompd Rad. 1985, 22, 1045; Oade, S.; Shinhama, K.; Kim, Y. H., Bull ChemSoc. Jpn. 1980, 53, 2023; Baker, B. R.; et al, J. Org Chem. 1952, 17,164) to yield corresponding compounds of formula V where one of thesubstituents is lower alkyl thio, perfluoro-lower alkyl thio and theother is hydrogen. If desired, the lower alkyl thio or perfluoro-loweralkyl thio compounds can then be converted to the corresponding loweralkyl sulfonyl or perfluoro-lower alkyl sulfonyl substituted compoundsof formula V by oxidation. Any conventional method of oxidizing alkylthio substituents to sulfones can be utilized to effect this conversion.If it is desired to produce compounds of lower alkyl or perfluoro-loweralkyl groups of compounds of formula V, the corresponding halosubstituted compounds of formula V can be used as starting materials.Any conventional method of converting an aromatic halo group to thecorresponding alkyl group (see for example, Katayama, T.; Umeno, M.,Chem. Lett. 1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3,630; Novak, J.; Salemink, C. A., Synthesis, 1983, 7, 597; Eapen, K. C.;Dua, S. S.; Tamboroski, C., J. Org. Chem. 1984, 49, 478; Chen, Q, -Y.;Duan, J. -X. J. Chem. Soc. Chem. Comm. 1993, 1389; Clark, J. H.;McClinton, M. A.; Jone, C. W.; Landon, P.; Bisohp, D.; Blade, R. J.,Tetrahedron Lett. 1989, 2133; Powell, R. L.; Heaton, C. A, U.S. Pat. No.5,113,013) can be utilized to effect this conversion. On the other hand,the thio substituent can be oxidized to a —SO₃H group which then can beconverted to —SO₂Cl which is reacted with ammonia to form thesulfonamide substituent —S(O)₂—NH₂.

[0099] For compounds of formula V where one of R¹ and R² is hydrogen andthe other is lower alkoxy lower alkyl sulfonyl, the corresponding thiolcompound may be used as a starting material. The compound of formula Vwhere one of R¹ and R² is hydrogen and the other is thiol may bealkoxylated by conventional methods (for example with alkoxy alkylhalide) to the corresponding lower alkoxy lower alkyl sulfanyl offormula V, which is then hydrolyzed by conventional methods (for examplewith lithium hydroxide, water, and tetrahydrofuran or sodium hydroxideand methanol) to the corresponding carboxylic acid. The latter isalkylated by conventional methods to add the desired methyl-cycloalkylR³ substituent. The resulting compound is oxidized by conventionalmethods at the sulfanyl to provide lower alkoxy lower alkyl sulfonylcompound of formula XII.

[0100] Conversion of the compound of formula XII to a compound offormula I-a′ is described below.

[0101] For compounds of formula V wherein one or both of R¹ and R² ishydroxyamino, the corresponding nitro compounds can be used as startingmaterial and can be converted to the corresponding compounds where R¹and/or R² are hydroxyamino. Any conventional method of converting anitro group to the corresponding aromatic hydroxyamino compound can beused to affect this conversion.

[0102] The carboxylic acids or esters of formula V wherein both of R¹and R² are chloro, or fluoro are commercially available. In cases, whereonly the carboxylic acids are available, they can converted to thecorresponding esters of lower alkyl alcohols using any conventionalesterification method. To produce the compound of formula V where bothR¹ and R² are nitro, 3,4-dinitrotoluene can be used as startingmaterial. This compound can be converted to the corresponding3,4-dinitrophenyl acetic acid. This conversion can take place eitherbefore or after the compound of formula V is converted to the compoundof formula 1-a′. Any conventional method of converting an aryl methylgroup to the corresponding aryl acetic acid can be utilized to effectthis conversion (see for example, Clark, R. D.; Muchowski, J. M.;Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M, Synthesis,1991, 871). The compounds of formula V where both R¹ and R² substituentsare amino can be obtained from the corresponding dinitro compound offormula V, described above. Any conventional method of reducing a nitrogroup to an amine can be utilized to effect this conversion. Thecompound of formula V where both R¹ and R² are amine groups can be usedto prepare the corresponding compound of formula V where both R¹ and R²are iodine or bromine via a diazotization reaction. Any conventionalmethod of converting amino group to an iodo or bromo group (see forexample, Lucas, H. J.; Kennedy, E. R. Org. Synth. Coll. Vol, II 1943,351) can be utilized to effect this conversion. If it is desired toproduce compounds of formula V where both R¹ and R² are lower alkyl thioor perfluoro-lower alkyl thio groups, the compound of formula V where R¹and R² are amino can be used as starting material. Any conventionalmethod of converting aryl amino group to aryl thioalkyl group can beutilized to effect this conversion. If it is desired to produce compoundof formula V where R¹ and R² are lower alkyl sulfonyl or lower perfluoroalkyl sulfonyl, the corresponding compounds of formula V where R¹ and R²are lower alkyl thio or perfluoro-lower alkyl thio can be used asstarting material. Any conventional method of oxidizing alkyl thiosubstituents to sulfones can be utilized to effect this conversion. Ifit is desired to produce compounds of formula V where both R¹ and R² aresubstituted with lower alkyl or perfluoro-lower alkyl groups, thecorresponding halo substituted compounds of formula V can be used asstarting materials. Any conventional method of converting an aromatichalo group to the corresponding alkyl or perfluoro-lower alkyl group canbe utilized to effect this conversion.

[0103] The carboxylic acids corresponding to the compounds of formula Vwhere one of R¹ and R² is nitro and the other is halo are known from theliterature (see for 4-chloro-3-nitrophenyl acetic acid, Tadayuki, S.;Hiroki, M.; Shinji, U.; Mitsuhiro, S. Japanese patent, JP 71-99504,Chemical Abstracts 80:59716; see for 4-nitro-3-chlorophenyl acetic acid,Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J. Org.Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J. TetrahedronLett. 1995, 36, 1279). These carboxylic acids can be converted to thecorresponding lower alkyl esters using any conventional esterificationmethods. Thus, if it is desired to produce the compound of formula Vwhere one of R¹ and R² is nitro and the other is lower alkyl thio orperfluoro-lower alkyl thio, the corresponding compound where one of R¹and R² is nitro and the other is chloro can be used as startingmaterial. In this reaction, any conventional method of nucleophilicdisplacement of aromatic chlorine group with a lower alkyl thiol can beused (see for example, Singh, P.; Batra, M. S.; Singh, H, J Chem. Res.-S1985 (6), S204; Ono, M.; Nakamura, Y.; Sata, S.; Itoh, I, Chem. Lett,1988, 1393; Wohrle, D.; Eskes, M.; Shigehara, K.; Yamada, A, Synthesis,1993, 194; Sutter, M.; Kunz, W, U.S. patent, U.S. Pat. No. 5,169,951).Once the compounds of formula V where one of R¹ and R² is nitro and theother is lower alkyl thio or perfluoro-lower alkyl thio are available,they can be converted to the corresponding compounds of formula V whereone of R¹ and R² is nitro and the other is lower alkyl sulfonyl orperfluoro-lower alkyl sulfonyl using conventional oxidation procedures.If it is desired to produce compounds of formula V where one of R¹ andR² is amino and the other is lower alkyl thio or perfluoro-lower alkylthio, the corresponding compound where one of R¹ and R² is nitro and theother is lower alkyl thio or perfluoro-lower alkyl thio can be used asstarting materials. Any conventional method of reducing an aromaticnitro group to an amine can be utilized to effect this conversion. If itis desired to produce compounds of formula V where one of R¹ and R² islower alkyl thio and the other is perfluoro-lower alkyl thio, thecorresponding compound where one of R¹ and R² is amino and the other islower alkyl thio or perfluoro-lower alkyl thio can be used as startingmaterials. Any conventional method of diazotizing aromatic amino groupand reacting it in situ with the desired lower alkyl thiol can beutilized to effect this conversion. If it is desired to producecompounds of formula V where one of R¹ and R² is lower alkyl sulfonyland the other is perfluoro-lower alkyl sulfonyl, the correspondingcompounds where one of R¹ and R² is lower alkyl thio and the other isperfluoro-lower alkyl thio can be used as starting materials. Anyconventional method of oxidizing an aromatic thio ether group to thecorresponding sulfone group can be utilized to effect this conversion.If it is desired to produce compounds of formula V where one of R¹ andR² is halo and the other is lower alkyl thio or perfluoro-lower alkylthio, the corresponding compounds where one of R¹ and R² is amino andthe other is lower alkyl thio or perfluoro-lower alkyl thio can be usedas starting materials. Any conventional method of diazotizing anaromatic amino group and conversion of it in situ to an aromatic halidecan be utilized to effect this conversion. If it is desired to producecompounds of formula V where one of R¹ and R² is halo and the other islower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, thecorresponding compounds where one of R¹ and R² is halo and the other islower alkyl thio or perfluoro-lower alkyl thio can be used as startingmaterials. Any conventional method of oxidizing an aromatic thio etherto the corresponding sulfone can be utilized to effect this conversion.If it is desired to produce compounds of various combinations of loweralkyl and perfluoro-lower alkyl groups of compounds of formula V, thecorresponding halo substituted compounds of formula V can be used asstarting materials. Any conventional method of converting an aromatichalo group to the corresponding alkyl group can be utilized to effectthis conversion. If one wishes to prepare the compound formula V whereone of R¹ and R² is nitro and the other is amino, the compound offormula V where one of R¹ and R² is nitro and other is chloro can beused as a starting material. The chloro substituent on the phenyl ringcan be converted to an iodo substituent (see for example, Bunnett, J.F.; Conner, R. M.; Org. Synth. Coll Vol V, 1973, 478; Clark, J. H.;Jones, C. W. J. Chem. Soc. Chem. Commun. 1987, 1409), which in turn canbe reacted with an azide transferring agent to form the correspondingazide (see for example, Suzuki, H.; Miyoshi, K.; Shinoda, M. Bull. Chem.Soc. Jpn, 1980, 53, 1765). This azide can then be reduced in aconventional manner to form the amine substituent by reducing it withcommonly used reducing agent for converting azides to amines (see forexample, Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis, 1987, 48).

[0104] If it is desired to produce the compound of formula V where bothR¹ and R² are cyano, this compound can be prepared as describedhereinbefore from compounds where R¹ and R² are amino via diazotizationto produce the diazonium salt followed by reaction with cyano grouptransferring agent. If it is desired to convert the commerciallyavailable compound to the compound of formula V where one of R¹ and R²is cyano and the other is not cyano, the compound of formula V where oneof R¹ and R² is nitro and the other is chloro is used as a startingmaterial. Using this starting material, the nitro is converted to thecyano and the halo is converted to any other desired R¹ and R²substituent as described hereinbefore.

[0105] If it is desired to produce the compound of formula V where bothR¹ and R² are lower alkoxy lower alkyl sulfonyl, the compound of formulaV where both R¹ and R² are amino can be used as starting material. Anyconventional method of converting an aryl amino group to an aryl thiogroup may be utilized to effect this conversion. The thio groups canthen be converted to lower alkoxy lower alkyl sulfonyl groups asdescribed above.

[0106] If it is desired to produce the compound of formula V wherein oneof R¹ or R² is a —C(O)—OR⁶, this compound can be formed from thecorresponding compound where R¹ and R² is an amino group by convertingthe amino group to a diazonium salt, reacting the diazonium salt with ahydrohalic acid to form the corresponding halide, and then reacting thishalide with a Grignard reagent to produce the corresponding acid whichcan be esterified. On the other hand, if one wants to produce thecompound of formula V where both R¹ and R² are carboxylic acid groups,this compound can be produced as described above from the correspondingcompound of formula V where both R¹ and R² are amino groups. In the samemanner, the amino groups in the compound of formula V can be convertedto the corresponding compound where R¹ or R² or both of R¹ and R² is OR⁵by simply reacting the amino group with sodium nitrate in sulfuric acidto convert the amino group to a hydroxy group and thereafteretherifying, if desired, the hydroxy group.

[0107] The substituents which form R¹ and R² can be added to the ringafter condensation after the compound of formula XII with the compoundof formula VIII to form the compound of formula I-a′. Hence, all of thereactions described to produce various substituents of R¹ and R² in thecompound of formula I can be carried out on the compound of formula I-a′after its formation by the reaction of compound of formula XII and VIIIto form the compound of formula I-a′.

[0108] In the first step of this Reaction Scheme, the alkyl halide offormula VI is reacted with the compound of formula V, to produce thecompound of formula VII. In this reaction, if in the compounds offormula V, R¹ or R² is an amino group, such amino group(s) have to beprotected before carrying out the alkylation reaction with the alkylhalide of formula VI. The amino group can be protected with anyconventional acid removable group (see for example, fort-butyloxycarbonyl group see, Bodanszky, M. Principles of PeptideChemistry, Springer-Verlag, New York, 1984, p 99). The protecting grouphas to be removed from the amino groups after preparing thecorresponding amine protected compounds of formula I-a′ to obtain thecorresponding amines. The compound of formula V is an organic acidderivative or the organic acid having an alpha carbon atom and thecompound of formula VI is an alkyl halide so that alkylation occurs atthe alpha carbon atom of this carboxylic acid. This reaction is carriedout by any conventional means of alkylation of the alpha carbon atom ofa carboxylic acid or a lower alkyl ester of a carboxylic acid.Generally, in these alkylation reactions any alkyl halide is reactedwith the anion generated from any acetic acid ester or the dianion ofthe acid. The anion can be generated by using a strong organic base suchas lithium diisopropylamide, n-butyl lithium as well as other organiclithium bases. In carrying out this reaction, low boiling ether solventsare utilized such as tetrahydrofuran at low temperatures from −80° C. toabout −10° C. being preferred. However any temperature from −80° C. toroom temperature can be used.

[0109] The compound of formula VII can be converted to the compound offormula XII by any conventional procedure to convert a carboxylic acidester to an acid. The compound of formula XII is condensed with thecompound of formula VIII via conventional peptide coupling to producethe compound of formula I-a′. In carrying out this reaction, anyconventional method of condensing a primary amine with a carboxylic acidcan be utilized to effect this conversion. The required aminoheteroaromatic compounds of formula VIII are commercially available orcan be prepared from the reported literature. The heteroaromatics offormula VIII, wherein one of the substitutions is —(CH₂)_(n)COOR⁶, wheren=0, 1, 2, 3, or 4 can be prepared from the corresponding carboxylicacid. Any conventional carbon homologation methods to convert a lowercarboxylic acid to its higher homologs, (see for example, Skeean, R. W.;Goel, O. P. Synthesis, 1990, 628) which then can be converted to thecorresponding lower alkyl esters using any conventional esterificationmethods. The heteroaromatics of formula VIII, wherein one of the claimedsubstitutions is —(CH₂)_(n)OR⁷, where n=0, 1, 2, 3, or 4 can be preparedfrom the corresponding carboxylic acid. Any conventional carbonhomologation methods to convert a lower carboxylic acid to its higherhomologs, which then can be converted to the corresponding alcoholsusing any conventional ester reduction methods. The heteroaromatics offormula VIII, wherein one of the substituents is —C(O)C(O)OR⁷, or—C(O)—OR⁶, can be prepared from the corresponding halogen. Anyconventional acylation method to convert an aromatic or heteroaromatichalogen to its oxoacetic acid lower ester or ester derivative (see forexample, Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett,1987, 28, 5895) can be utilized.

[0110] The compound of formula VII has an asymmetric carbon atom throughwhich the group —CH₂R³ and the acid amide substituents are connected. Inaccordance with this invention, the preferred stereoconfiguration ofthis group is R.

[0111] If it is desired to produce the R or the S isomer of the compoundof formula I, this compound can be separated into these isomers by anyconventional chemical means. Among the preferred chemical means is toreact the compound of formula XII with an optically active base. Anyconventional optically active base can be utilized to carry out thisresolution. Among the preferred optically active bases are the opticallyactive amine bases such as alpha-methylbenzylamine, quinine,dehydroabietylamine and alpha-methylnaphthylamine. Any of theconventional techniques utilized in resolving organic acids withoptically active organic amine bases can be utilized in carrying outthis reaction.

[0112] In the resolution step, the compound of formula XII is reactedwith the optically active base in an inert organic solvent medium toproduce salts of the optically active amine with both the R and Sisomers of the compound of formula XII. In the formation of these salts,temperatures and pressure are not critical and the salt formation cantake place at room temperature and atmospheric pressure. The R and Ssalts can be separated by any conventional method such as fractionalcrystallization. After crystallization, each of the salts can beconverted to the respective compounds of formula XII in the R and Sconfiguration by hydrolysis with an acid. Among the preferred acids aredilute aqueous acids , i.e., from about 0.001N to 2N aqueous acids, suchas aqueous sulfuric or aqueous hydrochloric acid. The configuration offormula XII which is produced by this method of resolution is carriedout throughout the entire reaction scheme to produce the desired R or Sisomer of formula I. The separation of R and S isomers can also beachieved using an enzymatic ester hydrolysis of any lower alkyl esterscorresponding to the compound of the formula XII (see for example,Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), whichresults in the formation of corresponding chiral acid and chiral ester.The ester and the acid can be separated by any conventional method ofseparating an acid from an ester. The preferred method of resolution ofracemates of the compounds of the formula XII is via the formation ofcorresponding diastereomeric esters or amides. These diastereomericesters or amides can be prepared by coupling the carboxylic acids of theformula XII with a chiral alcohol or a chiral amine. This reaction canbe carried out using any conventional method of coupling a carboxylicacid with an alcohol or an amine. The corresponding diastereomers ofcompounds of the formula XII can then be separated using anyconventional separation methods. The resulting pure diastereomericesters or amides can then be hydrolyzed to yield the corresponding pureR or S isomers. The hydrolysis reaction can be carried out usingconventional known methods to hydrolyze an ester or an amide withoutracemization.

[0113] All of the compounds of formula I which include the compounds setforth in the Examples activated glucokinase in vitro by the procedure ofExample A. In this manner, they increase the flux of glucose metabolismwhich causes increased insulin secretion. Therefore, the compounds offormula I are glucokinase activators useful for increasing insulinsecretion.

[0114] The following compounds were tested and found to have excellentglucokinase activator in vivo activity when administered orally inaccordance with the assay described in Example B:

[0115]3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0116]3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide

[0117]3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide

[0118]3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide

[0119]6-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid methyl ester

[0120]N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide

[0121]3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide

[0122]3-Cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide

[0123]3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)propionamide

[0124]6-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinicacid methyl ester

[0125]3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide

[0126] 3-Cyclopentyl -2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl -propionamide

[0127]2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0128]2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0129]2-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0130]2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0131] 1.N-(5-Bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

[0132]2-[3-Chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0133](2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide

[0134]2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0135] 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0136]3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0137]3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide

[0138]N-(5-Bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

[0139]3-Cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0140]3-Cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(4-methyl-thiazol-2-yl)-propionamide

[0141]3-Cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methyl-thiazol-2-yl)-propionamide

[0142]N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide

[0143]N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide

[0144]N-(5-Bromo-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide

[0145]2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(4-methyl-thiazol-2-yl)-propionamide

[0146]2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-propionamide

[0147]2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide

[0148]2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide

[0149]2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0150]2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0151]2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide

[0152]2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide

[0153]2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide

[0154]2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0155]2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide

[0156]3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamide

[0157]3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-propionamide

[0158]3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0159]3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamide

[0160]3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-propionamide

[0161]3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0162] This invention will be better understood from the followingexamples, which are for purposes of illustration and are not intended tolimit the invention defined in the claims which follow thereafter.

EXAMPLE 13-Cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide

[0163]

[0164] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(prepared as in Example 38A, 2.0 g, 6.96 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(4.62 g, 10.44 mmol), and 2-aminothiazole (1.05 g, 10.44 mmol) inmethylene chloride (50 mL) at 25° C. was treated with triethylamine (2.9mL, 20.88 mmol). The reaction mixture was stirred for 14 h. The reactionmixture was then diluted with water (10 mL) and extracted with methylenechloride (3×10 mL). The combined organic layers were sequentially washedwith water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL),a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturatedaqueous sodium chloride solution (1×10 mL). The organic layer was driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethylacetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide (2.48g, 96%) as a white solid: mp 143.5-145.5° C.; EI-HRMS m/e calcd forC₁₇H₁₈Cl₂N₂OS (M⁺) 368.0516, found 368.0516.

[0165] In an analogous manner, there were obtained:

[0166] a) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-(amino-thiazol-4-yl)-oxo-acetic acid ethyl ester:{2-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester as a white solid: mp 134-136° C.; FAB-HRMS m/e calcdfor C₂₁H₂₂Cl₂N₂O₄S (M+H)⁺ 469.0755, found 469.0746.

[0167] b) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-(amino-thiazol-5-yl)-oxo-acetic acid ethyl ester:{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-5-yl}-oxo-aceticacid ethyl ester as a white solid: mp 129-131° C.; FAB-HRMS m/e calcdfor C₂₁H₂₂Cl₂N₂O₄S (M+H)⁺ 469.0755, found 469.0765.

[0168] c) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and(2-amino-thiazol-4-yl)-acetic acid ethyl ester:{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester as a yellow solid: mp 138-139° C.; FAB-HRMS m/e calcdfor C₂₁H₂₄Cl₂N₂O₃S (M+H)⁺ 455.0963, found 455.0960.

[0169] d) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-amino-5-methylthiazole:3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-thiazol-2-yl)-propionamideas a white solid: mp 142-143° C.; EI-HRMS m/e calcd for C₁₈H₂₀Cl₂N₂OS(M⁺) 382.0673, found 382.0679.

[0170] e) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-amino-4-methylthiazole:3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methyl-thiazol-2-yl)-propionamideas a white foam: mp 151-152° C.; FAB-HRMS m/e calcd for C₁₈H₂₀Cl₂N₂OS(M+H)⁺ 383.0751, found 383.0758.

[0171] f) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-amino thiazole-4-carboxylic acid ethyl ester:2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester as a white solid: mp 104-107° C.; FAB-HRMS m/e calcdfor C₂₀H₂₂Cl₂N₂O₃S (M+H)⁺ 441.0807, found 441.0808.

[0172] g) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-amino-thiazole-5-carboxylic acid ethyl ester:2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid ethyl ester as a light yellow solid: mp 136-137° C.; FAB-HRMS m/ecalcd for C₂₀H₂₂Cl₂N₂O₃S (M+H)⁺ 441.0807, found 441.0803.

[0173] h) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-amino-5-nitrothiazole:3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro-thiazol-2-yl)-propionamideas an orange solid: mp 67-71° C.; FAB-HRMS m/e calcd for C₁₇H₁₇Cl₂N₃O₃S(M+H)⁺ 414.0446, found 414.0442.

[0174] i) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid and2-amino-thiazole-4-carboxylic acid amide:2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid amide as a light orange solid: mp 120-122° C.; EI-HRMS m/e calcdfor C₁₈H₁₉Cl₂N₃O₂S (M⁺) 411.0575, found 411.0572.

EXAMPLE 2 2-(4-Bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0175]

[0176] A solution of diisopropylamine (7.7 mL, 54.88 mmol) in drytetrahydrofuran (23 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to−78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (22.0 mL, 54.88 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-bromophenylacetic acid (5.62 g, 26.13 mmol) in drytetrahydrofuran (23 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The reactionmixture turned dark in color and was allowed to stir at −78° C. for 1 h,at which time, a solution of iodomethylcyclopentane (5.76 g, 27.44 mmol)in a small amount of dry tetrahydrofuran was added dropwise. Thereaction mixture was allowed to warm to 25° C. where it was stirred for24 h. The reaction mixture was quenched with water and then concentratedin vacuo to remove tetrahydrofuran. The aqueous residue was acidifiedusing a 10% aqueous hydrochloric acid solution. The resulting aqueouslayer was extracted with ethyl acetate (2×100 mL). The combined organicextracts were dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1hexanes/ethyl acetate) afforded2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (3.88 g, 50%) as a lightyellow solid: mp 91-93° C.; EI-HRMS m/e calcd for C₁₄H₁₇BrO₂ (M⁺)296.0412, found 296.0417.

[0177] A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid(1.01 g, 3.39 mmol) in methylene chloride (8.5 mL) was treated with 2drops of dry N,N-dimethylformamide. The reaction mixture was cooled to0° C. and then treated with oxalyl chloride (3 mL, 33.98 mmol). Thereaction mixture was stirred at 0° C. for 10 min and then stirred at 25°C. for 15 h. The reaction mixture was concentrated in vacuo. Theresulting yellow oil was dissolved in a small amount of methylenechloride and slowly added to a cooled solution (0° C.) of2-aminothiazole (680.6 mg, 6.79 mmol) and N,N-diisopropylethylamine (1.2mL, 6.79 mmol) in methylene chloride (17 mL). The resulting reactionmixture was stirred at 0° C. for 10 min and then at 25° C. for 15 h. Thereaction mixture was concentrated in vacuo to remove methylene chloride.The resulting residue was diluted with ethyl acetate (200 mL). Theorganic phase was washed with a 10% aqueous hydrochloric acid solution(2×100 mL), washed with a saturated aqueous sodium bicarbonate solution(2×100 mL), and washed with a saturated aqueous sodium chloride solution(1×100 mL). The organic layer was then dried over sodium sulfate,filtered, and concentrated in vacuo to afford2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (1.23 g,95%) as an orange solid which was used in subsequent reactions withoutfurther purification. An analytical sample was recrystallized from ethylacetate to provide a cream solid: mp 201-202° C.; EI-HRMS m/e calcd forC₁₇H₁₉BrN₂OS (M⁺) 378.0401, found 378.0405.

EXAMPLE 33-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0178]

[0179] A solution of diisopropylamine (3.3 mL, 23.5 mmol) in drytetrahydrofuran (50 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to−78° C. under nitrogen and then treated with a 10M solution ofn-butyllithium in hexanes (2.35 mL, 23.5 mmol). The yellow reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in asmall amount of dry tetrahydrofuran. After approximately one-half of the4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added, aprecipitate formed. Upon further addition of the remaining4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reactionmixture became thick in nature. After complete addition of the4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reactionmixture was very thick and became difficult to stir. An additionalamount of dry tetrahydrofuran (20 mL) was added to the thick reactionmixture, and the reaction mixture was then stirred at −78° C. for 45min, at which time, a solution of iodomethylcyclopentane (2.35 g, 11.2mmol) in a small amount of dry tetrahydrofuran was added dropwise. Thereaction mixture was allowed to warm to 25° C. where it was stirred for15 h. The reaction mixture was quenched with water (100 mL), and theresulting yellow reaction mixture was concentrated in vacuo to removetetrahydrofuran. The aqueous residue was acidified to pH=2 usingconcentrated hydrochloric acid. The aqueous layer was extracted withethyl acetate. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (1.80 g, 52%)as a white solid: mp 152-154° C.; EI-HRMS m/e calcd for C₁₅H₂₀O₄S (M⁺)296.1082, found 296.1080.

[0180] A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionicacid (4.91 g, 16.56 mmol) and triphenylphosphine (6.52 g, 24.85 mmol) inmethylene chloride (41 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (5.01 g, 28.16 mmol) in small portions. The reactionmixture color changed from light yellow to a darker yellow then tobrown. After the complete addition of N-bromosuccinimide, the reactionmixture was allowed to warm to 25° C. over 30 min. The brown reactionmixture was then treated with 2-aminothiazole (4.98 g, 49.69 mmol). Theresulting reaction mixture was stirred at 25° C. for 19 h. The reactionmixture was then concentrated in vacuo to remove methylene chloride. Theremaining black residue was diluted with a 10% aqueous hydrochloric acidsolution (400 mL) and then extracted with ethyl acetate (3×200 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×200 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(4.49 g, 72%) as a white solid: mp 216-217° C.; EI-HRMS m/e calcd forC₁₈H₂₂N₂O₃S₂ (M⁺) 378.1072, found 378.1071.

[0181] In an analogous manner, there were obtained:

[0182] a) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acidand 2-aminothiazole-4-carboxylic acid methyl ester:2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester as a tan solid: mp 126-128° C.; EI-HRMS m/e calcd forC₂₀H₂₄N₂O₅S₂ (M⁺) 436.1127, found 436.1119.

[0183] b) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acidand 2-aminothiazole-4-carboxylic acid ethyl ester:2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester as a light yellow solid: mp 101-103° C.; EI-HRMS m/ecalcd for C₂₁H₂₆N₂O₅S₂ (M⁺) 450.1283, found 450.1284.

[0184] c) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acidand methyl 2-amino-4-thiazoleacetate:{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester as a yellow solid: mp 63-65° C.; EI-HRMS m/e calcd forC₂₁H₂₆N₂O₅S₂ (M⁺) 450.1283, found 450.1294.

[0185] d) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acidand ethyl 2-amino-4-thiazoleacetate:{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester as a light yellow solid: mp 61-63° C.; EI-HRMS m/ecalcd for C₂₂H₂₈N₂O₅S₂ (M⁺) 464.1440, found 464.1431.

EXAMPLE 4 2-(4-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0186]

[0187] A solution of3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (preparedas in Example 22, 345 mg, 1.0 mmol) in ethyl acetate (100 mL) wastreated with 10% palladium on activated carbon (34.5 mg). The reactionmixture was stirred under hydrogen gas at 60 psi at 25° C. for 6 h. Thecatalyst was then filtered off through a pad of celite, which was washedwell with ethyl acetate. The resulting filtrate was concentrated invacuo to give2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (288.3 mg,91.4%) as a yellow solid: mp 102-107° C.; EI-HRMS m/e calcd forC₁₇H₂₁N₃OS (M⁺) 315.1405, found 315.1401.

EXAMPLE 5 2-(3-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0188]

[0189] A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) inmethanol (50 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 48 h. The reaction wasthen concentrated in vacuo. The residue was dissolved in methylenechloride (50 mL) and washed with a saturated aqueous sodium bicarbonatesolution (2×25 mL), water (1×50 mL), and a saturated aqueous sodiumchloride solution (1×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo to give(4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a paleyellow solid: mp 29-30° C.; EI-HRMS m/e calcd for C₉H₉NO₄ (M⁺) 195.0531,found 195.0532.

[0190] A solution of freshly prepared lithium diisopropylamide (43.3 mLof a 0.3M stock solution, 12.99 mmol) cooled to −78° C. was treated with(3-nitro-phenyl)-acetic acid methyl ester (2.45 g, 12.56 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (32mL, 3:1). The resulting solution was stirred at −78° C. for 45 min.Iodomethylcyclopentane (2.78 g, 13.23 mmol) was then added in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.78 mL), and themixture was stirred at −78° C. for 3 h. The reaction was warmed to 25°C. and was stirred at 25° C. for 16 h. The reaction mixture was thenquenched by the dropwise addition of a saturated aqueous ammoniumchloride solution (25 mL) and was concentrated in vacuo. The residue wasdiluted with water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with a saturated aqueous lithiumchloride solution (2×25 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh 80/20 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (1.63 g,46.8%) as pale yellow oil: EI-HRMS m/e calcd for C₁₅H₁₉NO₄ (M⁺)277.1314, found 277.1317.

[0191] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acidmethyl ester (0.55 g, 2.0 mmol) in tetrahydrofuran/water (10 mL, 3:1)was treated with lithium hydroxide (185 mg, 4.40 mmol). The reaction wasstirred at 25° C. for 48 h. The tetrahydrofuran was then removed invacuo. The residue was diluted with water (25 mL) and extracted withether (1×20 mL). The aqueous layer was acidified to pH=2 with a 3Naqueous hydrochloric acid solution. The product was extracted intomethylene chloride (3×25 mL). The combined organic layers were washedwith a saturated aqueous sodium chloride solution (2×25 mL), dried oversodium sulfate, filtered, and concentrated in vacuo to give3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid (0.48 g, 91.9%) as a tansolid: mp 95-99° C.; EI-HRMS m/e calcd for C₁₄H₁₇NO₄ (M⁺) 263.1157,found 263.1156.

[0192] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid(432 mg, 1.64 mmol) in methylene chloride (16 mL) was cooled to 0° C.and then treated with a 2.0M solution of oxalyl chloride in methylenechloride (0.90 mL, 1.80 mmol) and a few drops of N,N-dimethylformamide.The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for1.2 h. The reaction mixture was then treated with a solution of2-aminothiazole (361.4 mg, 3.61 mmol) in tetrahydrofuran (16 mL) andN,N-diisopropylethylamine (0.70 mL, 3.93 mmol). The reaction mixture wasstirred at 25° C. for 6 h. At this time, the reaction was concentratedin vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 70/30hexanes/ethyl acetate) afforded3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl-propionamide (409.3 mg,72.2%) as a tan solid: mp 171-174° C.; EI-HRMS m/e calcd for C₁₇H₁₉N₃O₃S(M⁺) 345.1147, found 345.1153.

[0193] A solution of3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl-propionamide (327.8 mg,0.95 mmol) in ethyl acetate (25 mL) was treated with 10% palladium onactivated carbon. The reaction mixture was stirred under hydrogen gas at60 psi at 25° C. for 3 h. The catalyst was then filtered off through apad of celite, which was washed well with ethyl acetate. The resultingfiltrate was concentrated in vacuo to give2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (310 mg,100%) as a white solid: mp 158-160° C.; EI-HRMS m/e calcd for C₁₇H₂₁N₃OS(M⁺) 315.1405, found 315.1405.

EXAMPLE 6 2-(3-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0194]

[0195] (3-Chloro-phenyl)-acetic acid (6.03 g, 0.03 mol) was dissolved inethanol (37.7 mL) and treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 12 h. The reaction wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded(3-chloro-phenyl)-acetic acid ethyl ester (6.10 g, 86.8%) as a clearoil: EI-HRMS m/e calcd for C₁₀H₁₁ClO₂(M⁺) 198.0448, found 198.0442.

[0196] A solution of freshly prepared lithium diisopropylamide (23 mL of0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with(3-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) intetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resultingsolution was stirred at −78° C. for 45 min. At this time, the reactionwas treated with a solution of iodomethylcyclopentane (1.50 g, 7.13mmol) in hexamethylphosphoramide (1 mL). The reaction mixture wasstirred at −78° C. for 4 h. The reaction was warmed to 25° C. andstirred at 25° C. for 16 h. The reaction mixture was then quenched bythe dropwise addition of a saturated aqueous ammonium chloride solution(20 mL). This mixture was poured into water (100 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethylacetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid ethylester (1.70 g, 93%) as a yellow oil: EI-HRMS m/e calcd for C₁₆H₂₁ClO₂(M⁺) 280.1230, found 280.1238.

[0197] A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acidethyl ester (1.70 g, 6.05 mmol) and methyl urea (673 mg, 9.08 mmol) in asolution of magnesium methoxide in methanol (7.4 wt %, 17.3 mL, 12.1mmol) was heated under reflux at 100° C. for 6 h. The reaction mixturewas then concentrated in vacuo. Flash chromatography (Merck Silica gel60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded1-[2-(3-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (149.1 mg,8%) as a white solid: mp 52-55° C.; EI-HRMS m/e calcd for C₁₆H₂₁ClN₂O₂(M⁺) 308.1292, found 308.1287. The methyl ester of the starting materialwas recovered from the reaction mixture due to transesterification.

[0198] A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acidmethyl ester (113 mg, 0.42 mmol) and 2-aminothiazole (84 mg, 0.84 mmol)in a solution of magnesium methoxide in methanol (7.4 wt %, 2.4 mL, 1.69mmol) was heated under reflux at 100° C. for 20 h. The reaction mixturewas then concentrated in vacuo. Flash chromatography (Merck Silica gel60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (87 mg,53%) as a white solid: mp 138.8-141.2° C.; EI-HRMS m/e calcd forC₁₇H₁₉ClN₂OS (M⁺) 334.0906, found 334.0907.

EXAMPLE 7 2-(4-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0199]

[0200] A solution of (4-chloro-phenyl)-acetic acid (6.29 g, 0.03 mol) inethanol (38.4 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 12 h. The reaction wasthen concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded(4-chloro-phenyl)-acetic acid ethyl ester (6.45 g, 88%) as a pale yellowsolid: mp 39-41° C.; EI-HRMS m/e calcd for C₁₀H₁₁ClO₂ (M⁺) 198.0448,found 198.0452.

[0201] A solution of freshly prepared lithium diisopropylamide (23.0 mLof 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with(4-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) intetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resultingsolution was stirred at −78° C. for 45 min. At this time, the reactionwas treated with a solution of iodomethylcyclopentane (1.50 mg, 7.13mmol) in hexamethylphosphoramide (1 mL). The reaction mixture wasstirred at −78° C. for 4 h. The reaction was warmed to 25° C. andstirred at 25° C. for 16 h. The reaction mixture was then quenched bythe dropwise addition of a saturated aqueous ammonium chloride solution(20 mL). This mixture was poured into water (100 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethylacetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethylester (1.65 g, 90.9%) as a yellow oil: EI-HRMS m/e calcd forC₁₆H₂₁Cl₂O₂(M⁺) 280.1230, found 280.1227.

[0202] A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acidethyl ester (1.65 g, 5.89 mmol) and methyl urea (654 mg, 8.83 mmol) in asolution of magnesium methoxide in methanol (7.4 wt %, 16.9 mL, 11.78mmol) was heated under reflux at 100° C. for 6 h. The reaction mixturewas then concentrated in vacuo. Flash chromatography (Merck Silica gel60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (105.3 mg,5.8%) as a white solid: mp 145-147° C.; EI-HRMS m/e calcd forC₁₆H₂₁ClN₂O₂ (M⁺) 308.1292, found 308.1291. The methyl ester of thestarting material was recovered from the reaction mixture due totransesterification.

[0203] A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acidmethyl ester (648 mg, 2.43 mmol) and 2-aminothiazole (487 mg, 4.86 mmol)in a solution of magnesium methoxide in methanol (7.4 wt %, 14.0 mL,9.72 mmol) was heated under reflux at 100° C. for 20 h. The reactionmixture was then concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (286 mg,35%) as a white solid: mp 156.6-159.8° C.; EI-HRMS m/e calcd forC₁₇H₁₉ClN₂OS (M⁺) 334.0906, found 334.0910.

EXAMPLE 83-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide

[0204]

[0205] A solution of freshly prepared lithium diisopropylamide (23 mL ofa 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with(4-trifluoromethyl-phenyl)-acetic acid (693 mg, 3.4 mmol) intetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resultingsolution was stirred at −78° C. for 30 min. Iodomethylcyclopentane (784mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). Themixture was stirred at −78° C. for 4 h. The reaction was then warmed to25° C. and was stirred at 25° C. for 16 h. The reaction mixture was thenquenched by the dropwise addition of a saturated aqueous ammoniumchloride solution (10 mL). The excess solvent was removed in vacuo. Theresidue was acidified to pH=1 with a 1N aqueous hydrochloric acidsolution. The mixture was then poured into water (150 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethylacetate) afforded 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionicacid (634.9 mg, 65%) as a white solid: mp 94-95° C.; EI-HRMS m/e calcdfor C₁₅H₁₇F₃O₂ (M⁺) 309.1079, found 309.1072.

[0206] A solution of3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (185 mg, 0.64mmol) in methylene chloride (6.5 mL) was cooled to 0° C. and was treatedwith a 2.0M solution of oxalyl chloride in methylene chloride (0.35 mL,0.71 mmol) and a few drops of N,N-dimethylformamide. The reactionmixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. Thereaction mixture was then treated with a solution of 2-aminothiazole(142 mg, 1.42 mmol) in tetrahydrofuran (3.23 mL) andN,N-diisopropylethylamine (0.27 mL, 1.55 mmol). The solution was stirredat 25° C. for 5 h. At this time, the reaction was concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20hexanes/ethyl acetate) afforded3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide(127 mg, 53.3%) as a white solid: mp 210-212° C.; EI-HRMS m/e calcd forC₁₈H₁₉F₃N₂OS (M⁺) 368.1175, found 368.1170.

EXAMPLE 93-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide

[0207]

[0208] A solution of diisopropylamine (3.2 mL, 23.16 mmol) in drytetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooledto −78° C. under nitrogen and then treated with a 10M solution ofn-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) indry tetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). Thereaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas then stirred at −78° C. for 30 min and then allowed to warm to 25°C. where it was stirred for 24 h. The reaction mixture was quenched withwater and then concentrated in vacuo to remove tetrahydrofuran. Theremaining aqueous phase was acidified to pH=2 with a 10% aqueoushydrochloric acid solution and then extracted with ethyl acetate (1×200mL). The organic layer was washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) asa cream solid: mp 91-93° C.; EI-HRMS m/e calcd for C₁₅H₂₀O₂S (M⁺)264.1184, found 264.1177.

[0209] A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionicacid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) inmethylene chloride (2 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After thecomplete addition of N-bromosuccinimide, the reaction mixture wasallowed to warm to 25° C. over 30 min. The reaction mixture was thentreated with 2-aminothiazole (160 mg, 1.60 mmol), and the resultingreaction mixture was stirred at 25° C. for 15 h. The reaction mixturewas then concentrated in vacuo to remove methylene chloride. Theremaining residue was diluted with water and ethyl acetate. The organiclayer was further washed with a 1N aqueous hydrochloric acid solutionand a saturated aqueous sodium bicarbonate solution, dried overmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethylacetate) afforded crude3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide asa yellow solid. Recrystallization from 2/1 hexanes/ethyl acetateafforded pure3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide(114 mg, 44%) as a white solid: mp 195-196° C.; EI-HRMS m/e calcd forC₁₈H₂₂N₂OS₂ (M⁺) 346.1174, found 346.1171.

EXAMPLE 103-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide

[0210]

[0211] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in drytetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooledto −78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00mmol) in dry tetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). Thereaction mixture was allowed to stir at −78° C. for 55 min, at whichtime, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to 25° C. where it was stirred for 41 h. Thereaction mixture was quenched with water and then concentrated in vacuoto remove tetrahydrofuran. The remaining aqueous phase was acidified topH=2 with a 10% aqueous hydrochloric acid solution and then extractedwith ethyl acetate (1×300 mL). The organic layer was washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₂S (M⁺) 318.0901, found 318.0912.

[0212] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (60 mg,0.19 mmol) and triphenylphosphine (49.4 mg, 0.19 mmol) in methylenechloride (471 μL) was cooled to 0° C. and then treated withN-bromosuccinimide (36.9 mg, 0.21 mmol) in small portions. After thecomplete addition of N-bromosuccinimide, the reaction mixture wasallowed to warm to 25° C. over 30 min. The bright orange reactionmixture was then treated with 2-aminothiazole (39.6 mg, 0.40 mmol). Theresulting reaction mixture was stirred at 25° C. for 18 h. The reactionmixture was then concentrated in vacuo to remove methylene chloride. Theremaining residue was diluted with ethyl acetate (50 mL). The organiclayer was washed sequentially with a 10% aqueous hydrochloric acidsolution (1×50 mL), a saturated aqueous sodium bicarbonate solution(1×50 mL) and water (1×50 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 9/1 hexanes/ethyl acetate) afforded3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-sulfanyl-phenyl)-propionamide(49.9 mg, 66%) as a white foam: mp 58-60° C.; EI-HRMS m/e calcd forC₁₈H₁₉F₃N₂OS₂ (M⁺) 400.0890, found 400.0895.

EXAMPLE 113-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide

[0213]

[0214] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in drytetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooledto −78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00mmol) in dry tetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). Thereaction mixture was allowed to stir at −78° C. for 55 min, at whichtime, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to 25° C. where it was stirred for 41 h. Thereaction mixture was quenched with water and then concentrated in vacuoto remove tetrahydrofuran. The remaining aqueous phase was acidified topH=2 with a 10% aqueous hydrochloric acid solution and then extractedwith ethyl acetate (1×300 mL). The organic layer was washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₂S (M⁺) 318.0901, found 318.0912.

[0215] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops ofconcentrated sulfuric acid. The resulting reaction mixture was heatedunder reflux for 36 h. The reaction mixture was allowed to cool to 25°C. and then concentrated in vacuo to remove methanol. The residue wasdiluted with ethyl acetate (200 mL). The organic phase was washed with asaturated aqueous sodium bicarbonate solution (1×100 mL), washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 97/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1052.

[0216] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.14 g, 3.43 mmol) in methylene chloride (8.6 mL) was treatedwith 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g based on 80%, 9.26mmol). The reaction mixture was stirred at 25° C. for 17 h, at whichtime, thin layer chromatography showed the presence of two new lowerR_(f) products. An additional 2.00 g of 3-chloroperoxybenzoic acid wasadded to the reaction mixture to drive the conversion of the sulfoxideto the sulfone, and the resulting reaction mixture was stirred at 25° C.for 3 d. The reaction mixture was concentrated in vacuo to removemethylene chloride. The resulting residue was diluted with ethyl acetate(300 mL). The organic phase was washed with a saturated aqueous sodiumbicarbonate solution (3×100 mL), washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 19/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (1.19 g, 95%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₄S (M⁺) 364.0956, found 364.0965.

[0217] A solution of3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was treated witha 0.8M aqueous lithium hydroxide solution (3.6 mL, 2.92 mmol). Thereaction mixture was stirred at 25° C. for 23 h and then concentrated invacuo to remove tetrahydrofuran. The remaining aqueous layer wasacidified to pH=2 with a 10% aqueous hydrochloric acid solution and thenextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with a saturated aqueous sodium chloride solution (1×100mL), dried over sodium sulfate, filtered, and concentrated in vacuo toafford a cream solid. This solid was purified by triturating withdiethyl ether/petroleum ether to provide pure3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (527.0mg, 77%) as a white solid: mp 143-145° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₄S (M⁺) 350.0800, found 350.0816.

[0218] A solution of3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (164.0mg, 0.47 mmol) and triphenylphosphine (184.2 mg, 0.70 mmol) in methylenechloride (1.2 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (141.6 mg, 0.80 mmol) in small portions. After thecomplete addition of N-bromosuccinimide, the reaction mixture wasallowed to warm to 25° C. where it was stirred for 1 h. The reactionmixture was then treated with 2-aminothiazole (140.6 mg, 1.40 mmol). Theresulting reaction mixture was stirred at 25° C. for 22 h. The reactionmixture was then concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide(47.9 mg, 24%) as a cream solid: mp 189-191° C.; EI-HRMS m/e calcd forC₁₈H₁₉F₃N₂O₃S₂ (M⁺) 432.0789, found 432.0791.

[0219] In an analogous manner, there were obtained:

[0220] a) From3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid and2-aminothiazole-4-carboxylic acid methyl ester:2-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester as a gray solid: mp 122-125° C.; EI-HRMS m/e calcd forC₂₀H₂₁F₃N₂O₅S₂ (M⁺) 490.0844, found 490.0844.

[0221] b) From3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid and2-aminothiazole-4-carboxylic acid ethyl ester:2-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester as a white solid: mp 132-134° C.; EI-HRMS m/e calcd forC₂₁H₂₃F₃N₂O₅S₂ (M⁺) 504.1000, found 504.0988.

[0222] c) From3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid andmethyl 2-amino-4-thiazoleacetate:{2-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester as a yellow foam: mp 48-52° C.; EI-HRMS m/e calcd forC₂₁H₂₃F₃N₂O₅S₂ (M⁺) 504.1000, found 504.0998.

EXAMPLE 122-[3-Chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0223]

[0224] A solution of anhydrous aluminum chloride (5.00 g, 37.50 mmol) inchloroform (15 mL) was cooled to 0° C. and stirred for 30 min under anitrogen atmosphere. A solution of ethyl oxalyl chloride (3.91 g, 28.64mmol) in chloroform (5 mL) was then added, and the resulting reactionmixture was stirred at 0° C. for an additional 30 min. A solution of2-chlorothioanisole (4.08 g, 25.58 mmol) in chloroform (20 mL) was thenslowly added to the cooled reaction mixture. The solution became red incolor and slowly became gum-like over a period of 30 min. The resultingreaction mixture was then stirred for an additional 3.5 h, and duringthis period, the reaction mixture was allowed to warm to 25° C. Thereaction mixture was then quenched by the addition of water (25 mL). Theaqueous layer was extracted with chloroform (3×25 mL). The combinedorganic layers were concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (4.32 g,65.3%) as a yellow oil.

[0225] A solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acidethyl ester (3.93 g, 15.19 mmol) in methanol (30 mL) was cooled to 0° C.and then treated with sodium borohydride (530.9 mg, 14.03 mmol). Thereaction mixture changed from yellow to colorless. The mixture wasstirred for 15 min and then quenched with a 1N aqueous hydrochloric acidsolution (10 mL). The resulting reaction mixture was then extracted withmethylene chloride (2×30 mL). The combined organic layers were washedwith a saturated aqueous sodium chloride solution (1×30 mL), dried oversodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 9/1 then 4/1hexanes/ethyl acetate) afforded(3-chloro-4-methylsulfanyl-phenyl)-hydroxy-acetic acid ethyl ester (1.43g, 38%) as a white solid: mp 56-57° C.; EI-HRMS m/e calcd forC₁₁H₁₃ClO₃S (M⁺) 260.0273, found 260.0276.

[0226] A solution of (3-chloro-4-methylsulfanyl-phenyl)-hydroxy-aceticacid ethyl ester (1.43 g, 5.49 mmol) in pyridine (2 mL) was treated withacetic anhydride (2 mL) and 4-dimethylaminopyridine (50 mg, 0.41 mmol).The reaction mixture was stirred at 25° C. for 16 h. The reactionmixture was then diluted with methylene chloride (100 mL). The organiclayer was washed with a 1N aqueous hydrochloric acid solution (2×30 mL),washed with a saturated aqueous sodium chloride solution (1×30 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethylacetate) afforded acetoxy-(3-chloro-4-methylsulfanyl-phenyl)-acetic acidethyl ester (1.51 g, 91%) as a light yellow oil: EI-HRMS m/e calcd forC₁₃H₁₅ClO₄S (M⁺) 302.0379, found 302.0387.

[0227] A solution of acetoxy-(3-chloro-4-methylsulfanyl-phenyl)-aceticacid ethyl ester (1.47 g, 4.87 mmol) in hexamethylphosphoramide (7.2 mL)and methanol (20 μL) was treated with a 0.1M solution of samarium iodidein tetrahydrofuran (146 mL, 14.6 mmol). The reaction mixture was stirredat 25° C. under nitrogen for 6 min. During this time period, thereaction mixture changed from purple to white. The reaction mixture wasdiluted with water (150 mL) and then extracted with methylene chloride(3×100 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded(3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (0.71 g, 60%)as a light yellow oil: EI-HRMS m/e calcd for C₁₁H₁₃ClO₂S (M⁺) 244.0324,found 244.0332.

[0228] A solution of diisopropylamine (457 μL, 3.26 mmol) intetrahydrofuran (5 mL) was cooled to −78° C. under a nitrogen atmosphereand then treated with a 2.5M solution of n-butyllithium in hexanes (1.3mL, 3.26 mmol). The mixture was stirred at −78° C. for 30 min, at whichtime, a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethylester (0.67 g, 2.75 mmol) in tetrahydrofuran (8 mL) was slowly added tothe reaction mixture. The reaction mixture turned deep yellow in color.The reaction mixture was then further stirred at −78° C. for 30 min, atwhich time, a solution of iodomethylcyclopentane (0.65 g, 3.09 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (1 mL) was added viasyringe. The reaction mixture was then allowed to warm to 25° C. whereit was stirred for 16 h. The reaction mixture turned red in color duringthis time period. The reaction mixture was quenched with a 6N aqueoushydrochloric acid solution (5 mL) and further diluted with water (20mL). The reaction mixture was then extracted with methylene chloride(3×20 mL). The combined organic layers were washed with a saturatedaqueous sodium chloride solution (1×25 mL), dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethylester (0.50 g, 56%) as a light yellow oil.

[0229] A solution of2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethylester (0.45 g, 1.39 mmol) in ethanol (3 mL) was treated with a 10%aqueous potassium hydroxide solution (2 mL). The reaction mixture wasstirred under nitrogen at 25° C. for 16 h. The reaction mixture was thenacidified with a 1N aqueous hydrochloric acid solution (5 mL). Thereaction mixture was then extracted with methylene chloride (3×15 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo to afford2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (0.29g, 70%) as a white solid: EI-HRMS m/e calcd for C₁₅H₁₉ClO₂S (M⁺)298.0794, found 298.0798.

[0230] A solution of benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.62 g, 1.41 mmol) and2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (0.29g, 0.95 mmol) in methylene chloride (10 mL) was treated withN,N-diisopropylethylamine (500 μL, 2.87 mmol) and 2-aminothiazole (140mg, 1.27 mmol). The mixture was stirred under nitrogen at 25° C. for 14h. The reaction mixture was then washed with a 6N aqueous hydrochloricacid solution (1×15 mL) and washed with a saturated aqueous sodiumchloride solution (1×25 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(0.26 g, 71%) as a white solid: EI-HRMS m/e calcd for C₁₈H₂₁ClN₂OS₂ (M⁺)380.0783, found 380.0792.

[0231] A solution of2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(187 mg, 0.49 mmol) in methylene chloride (10 mL) was cooled to 0° C.under nitrogen and then treated with 3-chloroperoxybenzoic acid (456.8mg based on 50% purity). The reaction mixture was stirred for 3 h, andduring this period, the temperature was allowed to warm to 25° C. Thereaction mixture was then diluted with methylene chloride (50 mL). Theorganic layer was washed with a saturated aqueous sodium carbonatesolution (1×20 mL), washed with a saturated aqueous sodium chloridesolution (1×20 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 hexanes/ethyl acetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(102 mg, 50%) as a white solid: EI-HRMS m/e calcd for C₁₈H₂₁ClN₂O₃S₂(M⁺) 412.0682, found 412.0674.

EXAMPLE 13(2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide

[0232]

[0233] A solution of 4-(methanesulfonyl)phenyl acetic acid (43.63 g,0.204 mol) in methanol (509 mL) was treated slowly with concentratedsulfuric acid (2 mL). The resulting reaction mixture was heated underreflux for 19 h. The reaction mixture was allowed to cool to 25° C. andthen concentrated in vacuo to remove methanol. The residue was dilutedwith ethyl acetate (800 mL). The organic phase was washed with asaturated aqueous sodium bicarbonate solution (1×200 mL), washed with asaturated aqueous sodium chloride solution (1×200 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded4-(methanesulfonyl)phenyl acetic acid methyl ester (45.42 g, 98%) as ayellow oil which solidified to a cream colored solid upon sitting overtime at 25° C.: mp 78-80° C.; EI-HRMS m/e calcd for C₁₀H₁₂O₄S (M⁺)228.0456, found 228.0451.

[0234] A mechanical stirrer was used for this reaction. A solution ofdiisopropylamine (29.2 mL, 0.21 mol) in dry tetrahydrofuran (186 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL) was cooled to−78° C. and then treated with a 2.5M solution of n-butyllithium inhexanes (83.4 mL, 0.21 mol). The yellow-orange reaction mixture wasstirred at −78° C. for 35 min and then slowly treated with a solution of4-(methanesulfonyl)phenyl acetic acid methyl ester (45.35 g, 0.20 mol)in dry tetrahydrofuran (186 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL). The reactionmixture turned dark in color. The reaction mixture was then stirred at−78° C. for 50 min, at which time, a solution of iodomethylcyclopentane(50.08 g, 0.24 mol) in a small amount of dry tetrahydrofuran was addedslowly. The reaction mixture was then stirred at −78° C. for 50 min, andthen allowed to warm to 25° C. where it was stirred for 36 h. Thereaction mixture was quenched with water (100 mL), and the resultingreaction mixture was concentrated in vacuo to remove tetrahydrofuran.The remaining residue was diluted with ethyl acetate (1.5 L). Theorganic phase was washed with a saturated aqueous sodium chloridesolution (1×500 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl ester(41.79 g, 68%) as a yellow viscous oil: EI-HRMS m/e calcd for C₁₆H₂₂O₄S(M⁺) 310.1239, found 310.1230.

[0235] A solution of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionicacid methyl ester (50.96 g, 0.16 mol) in methanol (410 mL) was treatedwith a 1N aqueous sodium hydroxide solution (345 mL, 0.35 mol). Thereaction mixture was stirred at 25° C. for 24 h. The reaction mixturewas concentrated in vacuo to remove methanol. The resulting aqueousresidue was acidified to pH=2 with concentrated hydrochloric acid andthen extracted with ethyl acetate (5×200 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo to afford pure 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionicacid (43.61 g, 90%) as a white solid which was used without furtherpurification: mp 152-154° C.; EI-HRMS m/e calcd for C₁₅H₂₀O₄S (M⁺)296.1082, found 296.1080.

[0236] Two separate reactions were setup in parallel: (1) A solution of(R)-(+)-4-benzyl-2-oxazolidinone (3.67 g, 20.73 mmol) in drytetrahydrofuran (35 mL) was cooled to −78° C. and then treated with a2.5M solution of n-butyllithium in hexanes (7.9 mL, 19.86 mmol). Theresulting reaction mixture was stirred at −78° C. for 30 min and thenallowed to warm to 25° C. where it was stirred for 1.5 h. (2) A solutionof racemic 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (5.12g, 17.27 mmol) in dry tetrahydrofuran (35 mL) was cooled to 0° C. andthen treated with triethylamine (2.8 mL, 19.86 mmol). The reactionmixture was stirred at 0° C. for 10 min and then treated dropwise withtrimethylacetyl chloride (2.6 mL, 20.73 mmol). The resulting reactionmixture was stirred at 0° C. for 2 h and then cooled to −78° C. for theaddition of the freshly prepared chiral oxazolidinone. The reactionmixture containing the oxazolidinone was then added to the cooled (−78°C.) mixed anhydride solution. The resulting reaction mixture was stirredas −78° C. for 1 h and allowed to gradually warm to 25° C. The reactionmixture was then stirred at 25° C. for 3 d. The resulting reactionmixture was quenched with water (100 mL) and then concentrated in vacuoto remove tetrahydrofuran. The resulting aqueous residue was dilutedwith ethyl acetate (600 mL). The organic layer was washed with asaturated aqueous sodium chloride solution (1×300 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Thin layer chromatographyusing 13/7 hexanes/ethyl acetate as the developing solvent indicated thepresence of two products. The higher moving product had a R_(f) =0.32and the lower moving product had a R_(f) =0.19. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 9/1 then 13/7 hexanes/ethyl acetate)afforded two products: (1) The higher R_(f) product (4R,2′S)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonylphenyl)propionyl]-oxazolidin-2-one(2.12 g, 54%) as a white foam: mp 62-64° C.; [α]²³ ₅₈₉ =+6.3° (c=0.24,chloroform); EI-HRMS m/e calcd for C₂₅H₂₉NO₅S (M⁺) 455.1766, found455.1757. (2) The lower R_(f) product (4R,2′R)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonylphenyl)propionyl]-oxazolidin-2-one(3.88 g, 99%) as a white foam: mp 59-61° C.; [α]²³ ₅₈₉=−98.3° (c=0.35,chloroform); EI-HRMS m/e calcd for C₂₅H₂₉NO₅S (M⁺) 455.1766, found455.1753. The combined mass recovery from the two products was 6.00 g,providing a 76% conversion yield for the reaction.

[0237] An aqueous solution of lithium hydroperoxide was freshly preparedfrom mixing a solution of anhydrous lithium hydroxide powder (707.3 mg,16.86 mmol) in 5.27 mL of water with a 30% aqueous hydrogen peroxidesolution (3.44 mL, 33.71 mmol). This freshly prepared aqueous lithiumhydroperoxide solution was cooled to 0° C. and then slowly added to acooled (0° C.) solution of (4R,2′R)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonylphenyl)propionyl]-oxazolidin-2-one(3.84 g, 8.43 mmol) in tetrahydrofuran (33 mL) and water (11 mL). Thereaction mixture was stirred 0° C. for 1.5 h. The reaction mixture wasthen quenched with a 1.5N aqueous sodium sulfite solution (25 mL). Thereaction mixture was further diluted with water (300 mL). The resultingaqueous layer was continuously extracted with diethyl ether until thinlayer chromatography indicated the absence of the recovered chiraloxazolidinone in the aqueous layer. The aqueous layer was then acidifiedto pH=2 with a 10% aqueous hydrochloric acid solution and extracted withethyl acetate (1×300 mL). The organic extract was dried over sodiumsulfate, filtered, and concentrated in vacuo to afford(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid as a whitesolid (2.23 g, 89%) which was used without further purification. Flashchromatography (Merck Silica gel 60, 70-230 mesh, 30/1 methylenechloride/methanol then 10/1 methylene chloride/methanol) was used toobtain a purified sample for analytical data and afforded pure(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid as a whitefoam: mp 62-64° C. (foam to gel); [α]²³ ₅₈₉=−50.0° (c=0.02, chloroform);EI-HRMS m/e calcd for C₁₅H₂₀O₄S (M⁺) 296.1082, found 296.1080.

[0238] A solution of triphenylphosphine (3.35 g, 12.79 mmol) inmethylene chloride (19 mL) was cooled to 0° C. and then slowly treatedwith N-bromosuccinimide (2.28 g, 12.79 mmol) in small portions. Thereaction mixture was stirred at 0° C. for 30 min, and during this timeperiod, the color of the reaction mixture changed from light yellow to adarker yellow then to a purple color. The cooled purple reaction mixturewas then treated with the(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (2.23 g,7.52 mmol). The resulting reaction mixture was then allowed to warm to25° C. over 45 min, at which time, the reaction mixture was then treatedwith 2-aminothiazole (1.88 g, 18.81 mmol). The resulting reactionmixture was stirred at 25° C. for 12 h. The reaction mixture was thenconcentrated in vacuo to remove methylene chloride. The remaining blackresidue was diluted with ethyl acetate (300 mL) and then washed wellwith a 10% aqueous hydrochloric acid solution (2×100 mL), a 5% aqueoussodium bicarbonate solution (3×100 mL), and a saturated aqueous sodiumchloride solution (1×200 mL). The organic layer was then dried oversodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 70-230 mesh, 9/1, 3/1, and then11/9 hexanes/ethyl acetate) afforded(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide(2.10 g, 74%) as a white foam: mp 78-80° C. (foam to gel); [α]²³ ₅₈₉=−70.4° (c=0.027, chloroform); EI-HRMS m/e calcd for C₁₈H₂₂N₂O₃S₂ (M⁺)378.1072, found 378.1081.

EXAMPLE 143-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide

[0239]

[0240] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32 mmol)in methanol (40 mL) was treated with Amberlyst® 15 ion exchange resin(15.00 g). The resulting reaction mixture was heated under reflux for 64h. The reaction mixture was allowed to cool to 25° C. and then filteredto remove the Amberlyst® 15 ion exchange resin. The filtrate wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 3/1 hexanes/ethyl acetate) afforded4-chloro-3-nitrophenylacetic acid methyl ester (1.91 g, 89%) as a yellowoil: EI-HRMS m/e calcd for C₉H₈ClNO₄ (M⁺) 229.0142, found 229.0146.

[0241] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in drytetrahydrofuran (45 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) was cooled to−78° C. and then treated dropwise with a 2.5M solution of n-butyllithiumin hexanes (9.56 mL, 23.9 mmol) over a 10 min period. The pale yellowreaction mixture was stirred at −78° C. for 20 min and then slowlytreated with a solution of 4-chloro-3-nitrophenylacetic acid methylester (5.00 g, 21.8 mmol) in a small amount of tetrahydrofuran over a 15min period. The reaction mixture turned deep purple (almost black) incolor. The reaction mixture was then stirred at −78° C. for 1 h, atwhich time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was then stirred at −78° C. and then allowed to warm to 25° C.where it was stirred for 48 h. The reaction mixture was quenched with asaturated aqueous ammonium chloride solution (50 mL), and the resultingreaction mixture was concentrated in vacuo to remove tetrahydrofuran.The remaining residue was diluted with ethyl acetate (150 mL) and water(50 mL). The organic phase was washed with a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 hexanes/ethyl acetate) afforded2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl ester(2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for C₁₅H₁₈ClNO₄ (M⁺)311.0924, found 311.0927.

[0242] A solution of 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionicacid methyl ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36g, 3.53 mmol) in dimethyl sulfoxide (3 mL) was heated at 130° C. for 5h. The black reaction mixture was then poured over ice (20 g), resultingin the formation of a brown sticky substance. The resulting mixture wasthen treated with ethyl acetate (50 mL) and water (50 mL), and thelayers were separated. The aqueous layer was further extracted withethyl acetate (2×50 mL). The combined organic layers were washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methylester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for C₁₆H₂₁NO₆S(M+H)⁺ 356.1169, found 356.1175.

[0243] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methylester (1.17 g, 3.29 mmol) in tetrahydrofuran (6 mL) was treated with a0.8M aqueous lithium hydroxide solution (6.17 mL, 4.94 mmol). Thereaction mixture was stirred at 25° C. for 3 h. The reaction mixture wasthen diluted with water (50 mL), a 1N aqueous hydrochloric acid solution(10 mL), and ethyl acetate (50 mL). The layers were separated, and theaqueous layer was back-extracted with ethyl acetate (2×50 mL). Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (993mg, 88%) as a yellow foam which contained a small impurity. A smallamount of the yellow foam (50 mg) was re-purified using Biotagechromatography (FLASH 40S, Silica, 3/1 then 1/1 hexanes/ethyl acetate)to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionicacid as a white foam: mp 114-118° C. (foam to gel); FAB-HRMS m/e calcdfor C₁₅H₁₉NO₆S (M+H)⁺ 342.1011, found 342.1014.

[0244] A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylenechloride (2 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (94 mg, 0.53 mmol) in small portions. The reactionmixture was stirred at 0° C. for 10 min and then treated with3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for5 min and then allowed to warm to 25° C. where it was stirred for 25min. The reaction mixture was then treated with 2-aminothiazole (97 mg,0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15h. The crude reaction mixture was directly purified by flashchromatography, (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate), to afford3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide(96 mg, 52%) as a pale yellow solid: mp 121-124° C.; FAB-HRMS m/e calcdfor C₁₈H₂₁N₃O₅S₂ (M+H)⁺ 424.1001, found 424.1000.

EXAMPLE 153-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide

[0245]

[0246] A solution of2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid ethyl ester (prepared as in Example 1(B)(g), 110 mg, 0.25 mmol) indiethyl ether (2 mL) at 0° C. was slowly treated with lithium aluminumhydride (12 mg, 0.31 mmol). The resulting reaction mixture continued tostir at 0° C. and was allowed to gradually warm to 25° C. The reactionmixture was then stirred at 25° C. over a period of 14 h. The reactionmixture was slowly quenched by the dropwise addition of water (5 mL).The resulting reaction mixture was partitioned between water and ethylacetate. A saturated aqueous sodium chloride solution was added to breakup the emulsions. The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide(52.9 mg, 53%) as a light yellow solid: mp 128-130° C.; EI-HRMS m/ecalcd for C₁₈H₂₀Cl₂N₂O₂S (M⁺) 398.0623, found 398.0623.

EXAMPLE 163-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-propionamide

[0247]

[0248] A solution of{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (prepared as in Example 1(B)(c), 129 mg, 0.28 mmol) intetrahydrofuran (1.4 mL) at 25° C. was slowly treated with sodiumborohydride (22.5 mg, 0.59 mmol). The resulting reaction mixture wasstirred at 25° C. for 10 h. After 10 h at 25° C., a substantial amountof starting material still remained. An additional amount of sodiumborohydride (21.4 mg, 0.57 mmol) was added to the reaction mixture, andthe reaction mixture was heated under reflux for 14 h. The reactionmixture was allowed to cool to 25° C. and then slowly quenched by thedropwise addition of water. The resulting reaction mixture wasconcentrated in vacuo to remove tetrahydrofuran. The resulting residuewas diluted with ethyl acetate (100 mL) and washed with a saturatedaqueous sodium chloride solution (1×50 mL). The organic layer was driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 3/1 then 1/1hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-propionamide(68.1 mg, 58%) as a white foam: mp 85-86° C.; FAB-HRMS m/e calcd forC₁₉H₂₂Cl₂N₂O₂S (M+H)⁺ 413.0858, found 413.0838.

EXAMPLE 173-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide

[0249]

[0250] A solution of2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester (prepared as in Example 1(B)(f), 200 mg, 0.45 mmol) intetrahydrofuran (3 mL) at 25° C. was slowly treated with sodiumborohydride (26.0 mg, 0.68 mmol). The reaction mixture was heated underreflux for 48 h. The reaction mixture was allowed to cool to 25° C. andthen slowly quenched by the dropwise addition of water. The resultingreaction mixture was partitioned between water and ethyl acetate. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide(44.9 mg, 25%) as a white solid: mp 88-90° C.; EI-HRMS m/e calcd forC₁₈H₂₀Cl₂N₂O₂S (M⁺) 398.0623, found 398.0631.

EXAMPLE 18{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid

[0251]

[0252] A solution of{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (prepared as in Example 1(B)(c), 198.1 mg, 0.44 mmol)in absolute ethanol (2.2 mL) was treated with a 1N aqueous sodiumhydroxide solution (910 μL, 0.91 mmol). The reaction mixture was heatedunder reflux for 2 h. The reaction mixture was allowed to cool to 25° C.and then concentrated in vacuo to remove absolute ethanol. The resultingresidue was acidified to pH=2 with a 10% aqueous hydrochloric acidsolution and extracted with ethyl acetate (1×150 mL). The organic layerwas washed with a saturated aqueous sodium chloride solution (1×100 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Theresulting white residue was washed well with cold water and dried toafford{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid (150 mg, 81%) as a white solid: mp 100-102° C.; FAB-HRMS m/e calcdfor C₁₉H₂₀Cl₂N₂O₃S (M+H)⁺ 427.0650, found 427.0633.

EXAMPLE 192-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid

[0253]

[0254] A solution of2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid ethyl ester (prepared as in Example 1(B)(g), 1.0 g, 2.27 mmol) inabsolute ethanol (10 mL) was treated with a 1N aqueous sodium hydroxidesolution (4.77 mL, 4.77 mmol). The reaction mixture was heated underreflux for 15 h. The reaction mixture was allowed to cool to 25° C. andthen concentrated in vacuo to remove absolute ethanol. The resultingyellow residue was acidified to pH=2 with concentrated hydrochloric acidand extracted with ethyl acetate (2×75 mL). The combined organic layerswere dried over magnesium sulfate, filtered, and concentrated in vacuo.Recrystallization from ethyl acetate afforded2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid (210 mg, 22%) as a white solid: mp 269-270° C.; FAB-HRMS m/e calcdfor C₁₈H₁₈Cl₂N₂O₃S (M+H)⁺ 413.0493, found 413.0483.

EXAMPLE 202-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid

[0255]

[0256] A solution of2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester (prepared as in Example 1(B)(f), 600 mg, 1.36 mmol) inabsolute ethanol (6 mL) was treated with a 1N aqueous sodium hydroxidesolution (2.85 mL, 2.85 mmol). The reaction mixture was heated underreflux for 15 h. The reaction mixture was allowed to cool to 25° C. andthen concentrated in vacuo to remove absolute ethanol. The resultingyellow residue was acidified to pH=2 with concentrated hydrochloric acidand extracted with ethyl acetate (2×100 mL). The combined organic layerswere dried over magnesium sulfate, filtered, and concentrated in vacuo.Precipitation from 1/1 hexanes/ethyl acetate afforded2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid (399 mg, 71%) as a white solid: mp 285-287° C.; FAB-HRMS m/e calcdfor C₁₈H₁₈Cl₂N₂O₃S (M+H)⁺ 413.0493, found 413.0481.

EXAMPLE 21{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester

[0257]

[0258] A solution of{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid (prepared as in Example 18, 95.4 mg, 0.223 mmol) in methanol (1.1mL) was treated with 1 drop of concentrated sulfuric acid. The reactionmixture was heated under reflux for 15 h. The reaction mixture wasallowed to cool to 25° C. and then concentrated in vacuo to removemethanol. The resulting residue was diluted with ethyl acetate (100 mL).The organic phase was washed with a saturated aqueous sodium chloridesolution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 3/1 hexanes/ethyl acetate) afforded{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester (77.2 mg, 78%) as a yellow viscous oil: FAB-HRMS m/ecalcd for C₂₀H₂₂Cl₂N₂O₃S (M+H)⁺ 441.0807, found 441.0804.

[0259] In an analogous manner, there were obtained:

[0260] a) From2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid (prepared as in Example 20):2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester as a white solid: mp 153-155° C.; FAB-HRMS m/e calcdfor C₁₉H₂₀Cl₂N₂O₃S (M+H)⁺ 427.0650, found 427.0659.

[0261] b) From2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid (prepared as in Example 19):2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid methyl ester as a white solid: mp 150-151° C.; FAB-HRMS m/e calcdfor C₁₉H₂₀Cl₂N₂O₃S (M+H)⁺ 427.0650, found 427.0650.

EXAMPLE 22 3-Cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide

[0262]

[0263] A solution of freshly prepared lithium diisopropylamide (430.55mL of a 0.3M stock solution, 129.16 mmol) cooled to −78° C. was treatedwith (4-nitro-phenyl)-acetic acid ethyl ester (26.32 g, 125.83 mmol) intetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The resultingsolution was stirred at −78° C. for 45 min. Iodomethylcyclopentane(27.75 g, 132.1 mmol) was then added in hexamethylphosphoramide (27.75mL). The mixture was stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 16 h. The reactionmixture was then quenched by the dropwise addition of a saturatedaqueous ammonium chloride solution (250 mL). This mixture wasconcentrated, diluted with water (250 mL), and extracted with ethylacetate (3×300 mL). The combined organic layers were washed with asaturated aqueous lithium chloride solution (2×250 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethylacetate) afforded 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethylester (28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for C₁₆H₂₁NO₄(M⁺) 291.1470, found 291.1470.

[0264] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acidethyl ester (14.1 g, 48.06 mmol) in tetrahydrofuran/water (300 mL, 3:1)was treated with lithium hydroxide (4.35 g, 103.67 mmol). The reactionwas stirred at 25° C. for 21 h. The tetrahydrofuran was then removed invacuo. The residue was diluted with water (75 mL) and extracted withether (3×75 mL). The aqueous layer was acidified to pH=1 with a 3Naqueous hydrochloric acid solution. The product was extracted intomethylene chloride (3×75 mL). The combined organic layers were washedwith a saturated aqueous sodium chloride solution (2×100 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo to give3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (11.97 g, 93.6%) as ayellow solid: mp 119-125° C.; EI-HRMS m/e calcd for C₁₄H₁₇NO₄ (M⁺)263.1157, found 263.1162.

[0265] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid(131 mg, 0.5 mmol) in methylene chloride (5.0 mL) was cooled to 0° C.and then treated with a 2.0M solution of oxalyl chloride in methylenechloride (1.0 mL, 2.0 mmol) and a few drops of N,N-dimethylformamide.The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for30 min. The reaction mixture was then treated with a solution of2-aminothiazole (110 mg, 1.0 mmol) in tetrahydrofuran (5 mL) andN,N-diisopropylethylamine (0.28 mL, 0.55 mmol). The solution was stirredat 25° C. for 24 h. At this time, the reaction was concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (38 mg,22.4%) as a yellow solid: mp 186-187° C.; EI-HRMS m/e calcd forC₁₇H₁₉N₃O₃S (M⁺) 345.1147, found 345.1148.

[0266] In an analogous manner, there was obtained:

[0267] a) From ethyl 2-amino-4-thiazole glyoxylate and3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid:{2-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester (57.5%) as a white solid: mp 134-136° C.; FAB-HRMS m/ecalcd for C₂₁H₂₃N₃O₆S (M+H)⁺ 446.1400, found 446.1386.

EXAMPLE 23{2-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester

[0268]

[0269] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid(prepared as in Example 22A, 263.0 mg, 1.0 mmol) inN,N-dimethylformamide (10 mL) was treated withO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(379 mg, 1.0 mmol), (2-amino-thiazol-4-yl)-acetic acid ethyl ester (279mg, 1.5 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). Thereaction mixture was stirred at 25° C. for 5 h. The reaction mixture wasthen poured into a 2N aqueous hydrochloric acid solution (25 mL) andextracted with ethyl acetate (3×25 mL). The combined organic layers werewashed with water (1×75 mL), a saturated aqueous sodium bicarbonatesolution (1×75 mL), and a saturated aqueous sodium chloride solution(3×75 mL), dried over sodium sulfate, filtered and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30hexanes/ethyl acetate) afforded{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (70.0 mg, 39.4%) as a pale yellow oil: FAB-HRMS m/ecalcd for C₂₁H₂₅N₃O₅S (M+H)⁺ 432.1593, found 432.1595.

EXAMPLE 24{2-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester

[0270]

[0271] A solution of{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (prepared as in Example 23, 160 mg, 0.37 mmol) inmethanol (10 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 68 h. The reaction wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 75/25 hexanes/ethyl acetate) afforded{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester (82.3 mg, 53.3%) as a pale yellow oil: FAB-HRMS m/ecalcd for C₂₀H₂₃N₃O₅S (M+H)⁺ 418.1436, found 418.1424.

EXAMPLE 25{2-[2-(4-Amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester

[0272]

[0273] A solution of{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester (prepared as in Example 24, 75.3 mg, 0.18 mmol) inethyl acetate (25 mL) was treated with 10% palladium on activatedcarbon. The reaction mixture was stirred under hydrogen gas at 60 psi at25° C. for 4 h. The catalyst was then filtered off through a pad ofcelite, which was washed well with ethyl acetate. The resulting filtratewas concentrated in vacuo to give{2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester (64.5 mg, 93.3%) as a tan oil: EI-HRMS m/e calcd forC₂₀H₂₅N₃O₃S (M⁺) 387.1616, found 387.1612.

EXAMPLE 262-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester

[0274]

[0275] A solution of2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester (prepared as in Example 39(B)(b), 135 mg, 0.32 mmol) inmethanol (10 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 68 h. The reaction wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester (71.4 mg, 54.8%) as a pale yellow solid: EI-HRMS m/ecalcd for C₁₉H₂₁N₃O₅S (M⁺) 403.1201, found 403.1188.

EXAMPLE 272-[2-(4-Amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester

[0276]

[0277] A solution of2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester (prepared as in Example 26, 60.0 mg, 0.14 mmol) inethyl acetate (25 mL) was treated with 10% palladium on activatedcarbon. The reaction mixture was stirred under hydrogen gas at 60 psi at25° C. for 4.5 h. The catalyst was then filtered off through a pad ofcelite, which was washed well with ethyl acetate. The resulting filtratewas concentrated in vacuo to give2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester (61.3 mg, 100%) as a pale yellow oil: EI-HRMS m/ecalcd for C₁₉H₂₃N₃O₃S (M⁺) 373.1460, found 373.1454.

EXAMPLE 28{2-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester

[0278]

[0279] A solution of freshly prepared lithium diisopropylamide (141.3 mLof a 0.32M stock solution, 45.0 mmol) cooled to −78° C. was treated with(3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7mL, 3:1). The resulting reaction solution was stirred at −78° C. for 1h. Iodomethylcyclopentane (4.64 g, 22.08 mmol) was then added in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). Thereaction mixture was stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 48 h. The solution wasthen quenched by the slow addition of the reaction mixture to a 2Naqueous hydrochloric acid solution (50 mL). The product was extractedinto ethyl acetate (1×150 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate)afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g,72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C₁₄H₁₇ClO₂(M⁺) 252.0917, found 252.0915.

[0280] A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid(252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. andthen treated with a 2.0M solution oxalyl chloride in methylene chloride(0.6 mL, 1.2 mmol) and a few drops of N,N-dimethylformamide. Thereaction mixture was stirred at 0° C. for 15 min and at 25° C. for 2 h.The reaction mixture was then treated with (2-amino-thiazol-4-yl)-aceticacid ethyl ester (409 mg, 2.2 mmol) and N,N-diisopropylethylamine (0.5mL, 2.4 mmol). This solution was stirred at 25° C. for 48 h. At thistime, the reaction was concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)afforded{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (254 mg, 60.3%) as a white solid: mp 121-125° C.;EI-HRMS m/e calcd for C₂₁H₂₅ClN₂O₃S (M⁺) 420.1274, found 420.1268.

[0281] In an analogous manner, there were obtained:

[0282] a) From 2-amino-thiazole-4-carboxylic acid ethyl ester and2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid:2-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid ethyl ester as a white solid: mp 167-168° C.; EI-HRMS m/e calcd forC₂₀H₂₃ClN₂O₃S (M⁺) 406.1117, found 406.1103.

[0283] b) From 2-amino-pyridine and2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid:2-(3-Chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide as a clearoil: EI-HRMS m/e calcd for C₁₉H₂₁ClN₂O (M⁺) 328.1342, found 328.1333.

[0284] c) From 6-amino-nicotinic acid methyl ester and2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid:6-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester as a colorless oil: EI-HRMS m/e calcd for C₂₁H₂₃ClN₂O₃ (M⁺)386.1397, found 386.1398.

EXAMPLE 29{2-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester

[0285]

[0286] A solution of{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (prepared as in Example 28A, 177.2 mg, 0.42 mmol) inmethanol (15 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 40 h. The reaction wasthen concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 70/30 hexanes/ethyl acetate) afforded{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester (104.4 mg, 60.9%) as a clear oil: EI-HRMS m/e calcdfor C₂₀H₂₃ClN₂O₃S (M⁺) 406.1117, found 406.1118.

EXAMPLE 302-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester

[0287]

[0288] A solution of2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid ethyl ester (prepared as in Example 28(B)(a), 94.5 mg, 0.23 mmol)in methanol (15 mL) was treated with a catalytic amount of sulfuricacid. The reaction mixture was heated under reflux for 40 h. Thereaction was then concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester (36.8 mg, 40.3%) as a white solid: mp 95-98° C.;EI-HRMS m/e calcd for C₁₉H₂₁ClN₂O₃S (M⁺) 392.0961, found 392.0989.

EXAMPLE 31{2-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester

[0289]

[0290] A solution of freshly prepared lithium diisopropylamide (78.0 mLof a 0.91M stock solution, 70.98 mmol) cooled to −78° C. was treatedwith (4-chloro-phenyl)-acetic acid (5.76 g, 33.8 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (84mL, 3:1). The resulting solution was stirred at −78° C. for 1 h.Iodomethylcyclopentane (7.45 g, 35.49 mmol) was then added in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). This solutionwas stirred at −78° C. for 4 h. The reaction was then warmed to 25° C.and was stirred at 25° C. for 16 h. The reaction mixture was thenquenched by the dropwise addition of a saturated aqueous ammoniumchloride solution (20 mL). The excess solvent was removed in vacuo. Theresidue was acidified to pH=1 with a 1N aqueous hydrochloric acidsolution. The mixture was then poured into water (150 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethylacetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (6.76g, 79.1%) as a yellow solid: mp 82-84° C.: EI-HRMS m/e calcd forC₁₄H₁₇ClO₂ (M⁺) 252.0917, found 252.0906.

[0291] A solution of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid(252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. andthen treated with a 2.0M solution of oxalyl chloride in methylenechloride (0.55 mL, 1.1 mmol) and a few drops of N,N-dimethylformamide.The reaction mixture was stirred at 0° C. for 15 min and then at 25° C.for 1.5 h. The reaction mixture was then treated with(2-amino-thiazol-4-yl)-acetic acid ethyl ester (409 mg, 2.2 mmol) andN,N-diisopropylethylamine (0.5 mL, 2.4 mmol). This solution was stirredat 25° C. for 24 h. At this time, the reaction was concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15hexanes/ethyl acetate) afforded{2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (183.3 mg, 43.5%) as a pale yellow oil: EI-HRMS m/ecalcd for C₂₁H₂₅ClN₂O₃S (M⁺) 420.1274, found 420.1272.

[0292] In an analogous manner, there were obtained:

[0293] a) From 2-amino-thiazole-4-carboxylic acid ethyl ester and2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid:2-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid ethyl ester as a white solid: mp 114-116° C.; EI-HRMS m/e calcd forC₂₀H₂₃ClN₂O₃S (M⁺) 406.1117, found 406.1119.

[0294] b) From 2-amino-pyridine and2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid:2-(4-Chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide as a clearoil: EI-HRMS m/e calcd for C₁₉H₂₁ClN₂O (M⁺) 328.1342, found 328.1355.

[0295] c) From 6-amino-nicotinic acid methyl ester and2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid:6-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester as a white foam: EI-HRMS m/e calcd for C₂₁H₂₃ClN₂O₃ (M⁺)386.1397, found 386.1384.

EXAMPLE 322-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester

[0296]

[0297] A solution of2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid ethyl ester (prepared as in Example 31(B)(a), 105 mg, 0.25 mmol) inmethanol (10 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 68 h. The reaction wasconcentrated in vacuo. High pressure liquid chromatography(Chromegasphere SI-60, 10 μm, 60 Å, 25 cm ×23 cm ID, 75/25 heptane/ethylacetate) afforded2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester (41.3 mg, 40.7%) as a white solid: mp 156-157° C.;EI-HRMS m/e calcd for C₁₉H₂₁ClN₂O₃S (M⁺) 392.0961, found 392.0956.

EXAMPLE 33{2-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester

[0298]

[0299] A solution of{2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (prepared as in Example 31A, 76.1 mg, 0.18 mmol) inmethanol (5 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 72 h. The reaction wasconcentrated in vacuo. High pressure liquid chromatography(Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23cm ID, 75/25 heptane/ethylacetate) afforded{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester (21.5 mg, 29.2%) as a colorless oil: EI-HRMS m/e calcdfor C₂₀H₂₃ClN₂O₃S (M⁺) 406.1117, found 406.1114.

EXAMPLE 342-(4-Chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide

[0300]

[0301] A solution of2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester (prepared as in Example 32, 127.7 mg, 0.31 mmol) intetrahydrofuran (0.4 mL) was added to a slurry of lithium aluminumhydride (15.0 mg, 0.39 mmol) in tetrahydrofuran (2.24 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 2 h. The reaction was thenquenched by the dropwise addition of water. The reaction was thendiluted with more water (25 mL) and extracted with ethyl acetate (3×25mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide(63.4 mg, 55.4%) as a white solid: mp 115-117° C.; EI-HRMS m/e calcd forC₁₈H₂₁ClN₂O₂S (M⁺) 364.1012, found 364.1004.

EXAMPLE 353-Cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide

[0302]

[0303] A solution of2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester (prepared as in Example 3(B)(b), 130 mg, 0.29 mmol) indiethyl ether (2 mL) was cooled to 0° C. and then slowly treated withlithium aluminum hydride (17 mg, 0.44 mmol). The reaction mixture wasallowed to warm to 25° C. where it was stirred for 4 h. After 4 h at 25°C., thin layer chromatography indicated the presence of startingmaterial. An additional amount of lithium aluminum hydride (11 mg, 0.29mmol) was added to the reaction mixture. The resulting reaction mixturewas allowed to stir at 25° C. for 15 h. The reaction mixture was thenslowly quenched by the dropwise addition of water. The resulting mixturewas then partitioned between water and ethyl acetate. The organic layerwas then dried over magnesium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ethylacetate) afforded3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide(55 mg, 46%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd forC₁₉H₂₄N₂O₄S₂ (M⁺) 408.11-78, found 408.1164.

EXAMPLE 363-Cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide

[0304]

[0305] A solution of{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (prepared as in Example 3(B)(d), 120 mg, 0.26 mmol) indiethyl ether (500 μL) was cooled to 0° C. and then slowly treated withlithium aluminum hydride (15 mg, 0.39 mmol). The reaction mixture wasallowed to warm to 25° C. where it was stirred for 1 h. After 1 h at 25°C., thin layer chromatography still indicated the presence of thestarting material. An additional amount of lithium aluminum hydride (10mg, 0.26 mmol) was added to the reaction mixture, and the reactionmixture was allowed to stir at 25° C. for 1 h. The reaction mixture wasthen slowly quenched by the dropwise addition of water (10 mL). Theresulting mixture was partitioned between water and ethyl acetate. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/3 hexanes/ethyl acetate) afforded3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide(20 mg, 18%) as a yellow foam: mp 84-87° C.; EI-HRMS m/e calcd forC₂₀H₂₆N₂O₄S₂ (M⁺) 422.1334, found 422.1335.

EXAMPLE 37(2R)-2-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester

[0306]

[0307] A solution triphenylphosphine (164 mg, 0.63 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (112 mg, 0.63 mmol) in small portions. The resultingorange reaction mixture was stirred at 0° C. for 20 min and then treatedwith 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (preparedas in Example 54A, 150 mg, 0.52 mmol). The reaction mixture was stirredat 0° C. for an additional 15 min and then allowed to warm to 25° C. Thereaction mixture was then treated with 2-aminothiazole-4-carboxylic acidmethyl ester (181 mg, 1.15 mmol). The resulting reaction mixture wasstirred at 25° C. for 15 h. The crude reaction mixture was directlypurified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1hexanes/ethyl acetate) to afford impure(2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester. The impure product was diluted with ethyl acetate andthen washed with a saturated aqueous sodium bicarbonate solution. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo to provide pure(2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester (92 mg, 41%) as a white solid: mp 143-144° C.; [α]²³₅₈₉=−10.2° (c=0.98, chloroform); EI-HRMS m/e calcd for C₁₉H₂₀Cl₂N₂O₃S(M⁺) 426.0572, found 426.0562.

EXAMPLE 383-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide

[0308]

[0309] A solution of triphenylphosphine (28.80 g, 109.8 mmol) andimidazole (14.9 g, 219.6 mmol) in methylene chloride (160 mL) was cooledto 0° C. and then slowly treated with iodine (27.87 g, 109.8 mmol). Thereaction mixture was then treated dropwise with a solution ofcyclopentylmethanol (10.0 g, 99.8 mmol) in methylene chloride (10 mL).The resulting reaction mixture was allowed to warm to 25° C. where itwas stirred for 4 h. The reaction mixture was then diluted with water(50 mL), and the reaction mixture was further extracted with methylenechloride (3×20 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo at 25° C. The resultingsolid was washed with pentane (4×50 mL) and filtered through a silicagel plug. The filtrate was concentrated in vacuo at 25° C. to affordiodomethylcyclopentane (18.48 g, 88%) as a clear colorless liquid:EI-HRMS m/e calcd for C₆H₁₁I₁ (M⁺) 209.9906, found 209.9911.

[0310] A solution of diisopropylamine (13.36 mL, 101.89 mmol) intetrahydrofuran (250 mL) was cooled to −78° C. under a nitrogenatmosphere and then treated with a 2.0M solution of n-butyllithium inhexanes (51 mL, 101.89 mmol). The reaction mixture was stirred at −78°C. for 15 min, at which time, a solution of 3,4-dichlorophenyl aceticacid (9.08 g, 44.3 mmol) in tetrahydrofuran (60 mL) andhexamethylphosphoramide (20 mL) was slowly added via a cannula. Thebright yellow solution was allowed to stir at −78° C. for 1 h, at whichtime, a solution of iodomethylcyclopentane (11.17 g, 53.2 mmol) inhexamethylphosphoramide (10 mL) was added via a cannula. The reactionmixture was stirred at −78° C. for 1 h. The reaction mixture was thenallowed to warm to 25° C. where it was stirred for 14 h. The reactionmixture was then acidified to pH=2 by the dropwise addition of a 1Naqueous hydrochloric acid solution and extracted with ethyl acetate(3×50 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, chloroform then 99/1 chloroform/methanol) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (10.28 g, 81%) as awhite solid: mp 74.5-76.9° C.; EI-HRMS m/e calcd for C₁₄H₁₆Cl₂O₂ (M⁺)286.0527, found 286.0534.

[0311] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(114 mg, 0.39 mmol) in methylene chloride (10 mL) was treated with 1drop of N,N-dimethylformamide and then cooled to 0° C. The reactionmixture was then treated with a 2.0M solution of oxalyl chloride inmethylene chloride (0.22 mL, 0.44 mmol). The reaction mixture wasstirred at 0° C. for 30 min and then treated with a solution of2-aminopyridine (78 mg, 0.83 mmol) and N,N-diisopropylethylamine (0.16mL, 0.95 mmol) in tetrahydrofuran (2 mL). The resulting reaction mixturewas stirred at 25° C. for 14 h. The reaction mixture was then dilutedwith water (10 mL) and extracted with methylene chloride (2×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, hexanes then 19/1 to 4/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide (58mg, 50%) as a white foam: EI-HRMS m/e calcd for C₁₉H₂₀Cl₂N₂O (M⁺)362.0953, found 362.0955.

[0312] In an analogous manner, there were obtained:

[0313] a) From 2-amino-5-nitropyridine and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-nitropyridin)-2-yl-propionamideas a yellow-orange foam: EI-HRMS m/e calcd for C₁₉H₁₉Cl₂N₃O₃ (M⁺)407.0803, found 407.0799.

[0314] b) From 6-aminonicotinic acid methyl ester and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-propionamideas a white foam: EI-HRMS m/e calcd for C₂₁H₂₂Cl₂N₂O₃ (M⁺) 420.1007,found 420.0994.

[0315] c) From 4-aminopyrimidine and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrimidine-4-yl-propionamide asa white foam: EI-HRMS m/e calcd for C₁₈H₁₉Cl₂N₃O (M⁺) 363.0905, found363.0910.

[0316] d) From 2-amino-5-methylpyridine and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-methylpyridin)-2-yl-propionamideas a white solid: EI-HRMS m/e calcd for C₂₀H₂₂Cl₂N₂O (M⁺) 376.1109,found 376.1119.

[0317] e) From 2-amino-4-methylpyridine and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4-methylpyridin)-2-yl-propionamideas a white solid: EI-HRMS m/e calcd for C₂₀H₂₂Cl₂N₂O (M⁺) 376.1109,found 376.1106.

[0318] f) From 2-amino-6-methylpyridine and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-methylpyridin)-2-yl-propionamideas a light yellow solid: EI-HRMS m/e calcd for C₂₀H₂₂Cl₂N₂O (M⁺)376.1109, found 376.1107.

[0319] g) From 2-amino-5-chloropyridine and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-chloropyridin)-2-yl-propionamideas a white foam: EI-HRMS m/e calcd for C₁₉H₁₉Cl₃N₂O (M⁺) 396.0563, found396.0564.

[0320] h) From 2-amino-5-bromopyridine and3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-bromopyridin)-2-yl-propionamideas a white solid: EI-HRMS m/e calcd for C₁₉H₁₉BrCl₂N₂O (M⁺) 440.0058,found 440.0066.

EXAMPLE 39 3-Cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide

[0321]

[0322] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid(prepared as in Example 22, 263 mg, 1.0 mmol) in methylene chloride (5mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalylchloride in methylene chloride (0.6 mL, 1.2 mmol) and a few drops ofN,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15min and then at 25° C. for 1 h. The reaction mixture was then treatedwith a solution of 2-aminopyridine (207 mg, 2.2 mmol) in tetrahydrofuran(5 mL) and N,N-diisopropylethylamine (0.42 mL, 2.5 mmol). The reactionmixture was stirred at 25° C. for 24 h. At this time, the reaction wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 80/20 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (110.2 mg,32.5%) as a white solid: mp 152-154° C.; EI-HRMS m/e calcd forC₁₉H₂₁N₃O₃ (M⁺) 339.1582, found 339.1581.

[0323] In an analogous manner, there were obtained:

[0324] a) From 4-aminopyrimidine and3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid:3-Cyclopentyl-2-(4-nitro-phenyl)-N-pyrimidin-4-yl-propionamide as awhite solid: mp 152-153° C.; EI-HRMS m/e calcd for C₁₈H₂₀N₄O₃ (M⁺)340.1535, found 340.1533.

[0325] b) From 2-amino-thiazole-4-carboxylic acid ethyl ester and3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid:2-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester as a pale yellow solid: mp 110-115° C.; EI-HRMS m/ecalcd for C₂₀H₂₃N₃O₅S (M⁺) 417.1358, found 417.1346.

EXAMPLE 403-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide

[0326]

[0327] A solution of diisopropylamine (3.2 mL, 23.16 mmol) in drytetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooledto −78° C. under nitrogen and then treated with a 10M solution ofn-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) indry tetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). Thereaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas then stirred at −78° C. for 30 min and then allowed to warm to 25°C. where it was stirred for 24 h. The reaction mixture was quenched withwater and then concentrated in vacuo to remove tetrahydrofuran. Theremaining aqueous phase was acidified to pH=2 with a 10% aqueoushydrochloric acid solution and then extracted with ethyl acetate (1×200mL). The organic layer was washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) asa cream solid: mp 91-93° C.; EI-HRMS m/e calcd for C₁₅H₂₀O₂S (M⁺)264.1184, found 264.1177.

[0328] A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionicacid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) inmethylene chloride (2 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After thecomplete addition of N-bromosuccinimide, the reaction mixture wasallowed to warm to 25° C. over 30 min. The orange reaction mixture wasthen treated with 2-aminopyridine (151 mg, 1.60 mmol), and the resultingreaction mixture was stirred at 25° C. for 15 h. The reaction mixturewas then concentrated in vacuo to remove methylene chloride. Theremaining residue was partitioned between water and ethyl acetate. Theorganic layer was washed with a 1N aqueous hydrochloric acid solution,washed with a saturated aqueous sodium bicarbonate solution, dried overmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethylacetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide(83 mg, 32%) as a white solid: mp 127-128° C.; EI-HRMS m/e calcd forC₂₀H₂₄N₂OS (M⁺) 340.1609, found 340.1611.

EXAMPLE 413-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide

[0329]

[0330] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in drytetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooledto −78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00mmol) in dry tetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). Thereaction mixture was allowed to stir at −78° C. for 55 min, at whichtime, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to 25° C. where it was stirred for 41 h. Thereaction mixture was quenched with water and then concentrated in vacuoto remove tetrahydrofuran. The remaining aqueous phase was acidified topH=2 with a 10% aqueous hydrochloric acid solution and then extractedwith ethyl acetate (1×300 mL). The organic layer was washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₂S (M⁺) 318.0901, found 318.0912.

[0331] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (59.6mg, 0.187 mmol) and triphenylphosphine (49.1 mg, 0.187 mmol) inmethylene chloride (468 μL) was cooled to 0° C. and then treated withN-bromosuccinimide (36.7 mg, 0.206 mmol) in small portions. After thecomplete addition of N-bromosuccinimide, the reaction mixture wasallowed to warm to 25° C. over 30 min. The orange reaction mixture wasthen treated with 2-aminopyridine (35.2 mg, 0.374 mmol). The resultingreaction mixture was stirred at 25° C. for 16 h. The reaction mixturewas then concentrated in vacuo to remove methylene chloride. Theremaining residue was diluted with ethyl acetate (50 mL). The organiclayer was washed sequentially with a 10% aqueous hydrochloric acidsolution (1×50 mL), a saturated aqueous sodium bicarbonate solution(1×50 mL) and water (1×50 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 9/1 hexanes/ethyl acetate) afforded3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide(25.0 mg, 34%) as a cream solid: mp 101-102° C.; EI-HRMS m/e calcd forC₂₀H₂₁F₃N₂OS (M⁺) 394.1327, found 394.1321.

EXAMPLE 423-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide

[0332]

[0333] A solution of 2-aminopyridine (95 mg, 1.01 mmol) in acetonitrile(2 mL) was treated with3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (prepared as inExample 3A, 250 mg, 0.84 mmol), triphenylphosphine (243 mg, 0.93 mmol),triethylamine (350 μL, 2.53 mmol), and carbon tetrachloride (1 mL). Theresulting reaction mixture was stirred at 25° C. for 15 h. The cloudyreaction mixture was diluted with water and then extracted withmethylene chloride. The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded impure3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide.Recrystallization from hexanes/methylene chloride provided pure3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide(170 mg, 54%) as a white solid: mp 172-173° C.; EI-HRMS m/e calcd forC₂₀H₂₄N₂O₃S (M⁺) 372.1508, found 372.1498.

EXAMPLE 433-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide

[0334]

[0335] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in drytetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooledto −78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00mmol) in dry tetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). Thereaction mixture was allowed to stir at −78° C. for 55 min, at whichtime, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to 25° C. where it was stirred for 41 h. Thereaction mixture was quenched with water and then concentrated in vacuoto remove tetrahydrofuran. The remaining aqueous phase was acidified topH=2 with a 10% aqueous hydrochloric acid solution and then extractedwith ethyl acetate (1×300 mL). The organic layer was washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₂S (M⁺) 318.0901, found 318.0912.

[0336] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops ofconcentrated sulfuric acid. The resulting reaction mixture was heatedunder reflux for 36 h. The reaction mixture was allowed to cool to 25°C. and then concentrated in vacuo to remove methanol. The residue wasdiluted with ethyl acetate (200 mL). The organic phase was washed with asaturated aqueous sodium bicarbonate solution (1×100 mL) and a saturatedaqueous sodium chloride solution (1×100 mL), dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 70-230 mesh, 97/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1052.

[0337] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.14 g, 3.43 mmol) in methylene chloride (8.6 mL) was treatedwith 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g based on 80%, 9.26mmol). The reaction mixture was stirred at 25° C. for 17 h, at whichtime, thin layer chromatography showed the presence of two new lowerR_(f) products. An additional 2.00 g of 3-chloroperoxybenzoic acid wasadded to the reaction mixture to drive the conversion of the sulfoxideto the sulfone, and the resulting reaction mixture was stirred at 25° C.for 3 d. The reaction mixture was concentrated in vacuo to removemethylene chloride. The resulting residue was diluted with ethyl acetate(300 mL). The organic phase was washed with a saturated aqueous sodiumbicarbonate solution (3×100 mL) and a saturated aqueous sodium chloridesolution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 19/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (1.19 g, 95%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₄S (M⁺) 364.0956, found 364.0965.

[0338] A solution of3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was treated witha 0.8M aqueous lithium hydroxide solution (3.6 mL, 2.92 mmol). Thereaction mixture was stirred at 25° C. for 23 h and then concentrated invacuo to remove tetrahydrofuran. The remaining aqueous layer wasacidified to pH=2 with a 10% aqueous hydrochloric acid solution and thenextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with a saturated aqueous sodium chloride solution (1×100mL), dried over sodium sulfate, filtered, and concentrated in vacuo toafford a cream solid. This solid was purified by triturating withdiethyl ether/petroleum ether to provide pure3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (527.0mg, 77%) as a white solid: mp 143-145° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₄S (M⁺) 350.0800, found 350.0816.

[0339] A solution of3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (118.9mg, 0.34 mmol) and triphenylphosphine (133.5 mg, 0.51 mmol) in methylenechloride (848 μL) was cooled to 0° C. and then treated withN-bromosuccinimide (102.7 mg, 0.58 mmol) in small portions. After thecomplete addition of N-bromosuccinimide, the reaction mixture wasallowed to warm to 25° C. where it was stirred for 45 min. The reactionmixture was then treated with 2-aminopyridine (95.8 mg, 1.02 mmol). Theresulting reaction mixture was stirred at 25° C. for 22 h. The reactionmixture was then concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 5/1 hexanes/ethyl acetate) afforded3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide(37.1 mg, 26%) as a light yellow solid: mp 151-153° C.; EI-HRMS m/ecalcd for C₂₀H₂₁F₃N₂O₃S (M⁺) 426.1225, found 426.1220.

[0340] In an analogous manner, there were obtained:

[0341] a) From3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid and2-amino-5-chloropyridine:N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethane-sulfonyl-phenyl)-propionamideas a cream solid: mp 146-148° C.; EI-HRMS m/e calcd for C₂₀H₂₀ClF₃N₂O₃S(M⁺) 460.0835, found 460.0846.

[0342] b) From3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid and2-amino-5-methyl pyridine:3-Cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoro-methanesulfonyl-phenyl)-propionamideas a pale yellow solid: mp 155-157° C.; EI-HRMS m/e calcd forC₂₁H₂₃F₃N₂O₃S (M⁺) 440.1381, found 440.1376.

[0343] c) From3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid and6-aminonicotinic acid methyl ester:6-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinicacid methyl ester as a yellow foam: mp 58-62° C.; EI-HRMS m/e calcd forC₂₂H₂₃F₃N₂O₅S (M⁺) 484.1280, found 484.1274.

EXAMPLE 443-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide

[0344]

[0345] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32 mmol)in methanol (40 mL) was treated with Amberlyst® 15 ion exchange resin(15.00 g). The resulting reaction mixture was heated under reflux for 64h. The reaction mixture was allowed to cool to 25° C. and then filteredto remove the Amberlyst® 15 ion exchange resin. The filtrate wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 3/1 hexanes/ethyl acetate) afforded4-chloro-3-nitrophenylacetic acid methyl ester (1.91 g, 89%) as a yellowoil: EI-HRMS m/e calcd for C₉H₈ClNO₄ (M⁺) 229.0142, found 229.0146.

[0346] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in drytetrahydrofuran (45 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) was cooled to−78° C. and then treated dropwise with a 2.5M solution of n-butyllithiumin hexanes (9.56 mL, 23.9 mmol) over a 10 min period. The pale yellowreaction mixture was stirred at −78° C. for 20 min and then slowlytreated with a solution of 4-chloro-3-nitrophenylacetic acid methylester (5.00 g, 21.8 mmol) in a small amount of tetrahydrofuran over a 15min period. The reaction mixture turned deep purple (almost black) incolor. The reaction mixture was then stirred at −78° C. for 1 h, atwhich time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was then stirred at −78° C. and then allowed to warm to 25° C.where it was stirred for 48 h. The reaction mixture was quenched with asaturated aqueous ammonium chloride solution (50 mL), and the resultingreaction mixture was concentrated in vacuo to remove tetrahydrofuran.The remaining residue was diluted with ethyl acetate (150 mL) and water(50 mL). The organic phase was washed with a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 hexanes/ethyl acetate) afforded2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl ester(2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for C₁₅H₁₈ClNO₄ (M⁺)311.0924, found 311.0927.

[0347] A solution of 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionicacid methyl ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36g, 3.53 mmol) in dimethyl sulfoxide (3 mL) was heated at 130° C. for 5h. The black reaction mixture was then poured over ice (20 g), resultingin the formation of a brown sticky substance. The resulting mixture wasthen treated with ethyl acetate (50 mL) and water (50 mL), and thelayers were separated. The aqueous layer was further extracted withethyl acetate (2×50 mL). The combined organic layers were washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methylester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for C₁₆H₂₁NO₆S(M+H)⁺ 356.1169, found 356.1175.

[0348] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methylester (1.17 g, 3.29 mmol) in tetrahydrofuran (6 mL) was treated with a0.8M aqueous lithium hydroxide solution (6.17 mL, 4.94 mmol). Thereaction mixture was stirred at 25° C. for 3 h. The reaction mixture wasthen diluted with water (50 mL), a 1N aqueous hydrochloric acid solution(10 mL), and ethyl acetate (50 mL). The layers were separated, and theaqueous layer was back-extracted with ethyl acetate (2×50 mL). Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (993mg, 88%) as a yellow foam which contained a small impurity. A smallamount of the yellow foam (50 mg) was re-purified using Biotagechromatography (FLASH 40S, Silica, 3/1 then 1/1 hexanes/ethyl acetate)to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionicacid as a white foam: mp 114-118° C. (foam to gel); FAB-HRMS m/e calcdfor C₁₅H₁₉NO₆S (M+H)⁺ 342.1011, found 342.1014.

[0349] A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylenechloride (2 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (94 mg, 0.53 mmol) in small portions. The reactionmixture was stirred at 0° C. for 10 min and then treated with3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for5 min and then allowed to warm to 25° C. where it was stirred for 25min. The reaction mixture was then treated with 2-aminopyridine (91 mg,0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15h. The crude reaction mixture was directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) to afford3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide(106 mg, 58%) as a white foam: mp 92-95° C. (foam to gel); FAB-HRMS m/ecalcd for C₂₀H₂₃N₃O₅S (M+H)⁺ 418.1436, found 418.1430.

EXAMPLE 456-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid methyl ester

[0350]

[0351] A mixture of 6-aminonicotinic acid (4.0 g, 28.9 mmol), methanol(75 mL), and concentrated hydrochloric acid (4 mL) was heated underreflux for 16 h. The reaction mixture was allowed to cool to 25° C. andthen concentrated in vacuo to remove methanol. The resulting solid wastreated with water (20 mL) and enough sodium bicarbonate to adjust thepH to pH=8. The solution was then extracted with ethyl acetate (3×25mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo to afford 6-aminonicotinic acidmethyl ester (3.12 g, 71%) as white foam: EI-HRMS m/e calcd for C₇H₈N₂O₂(M⁺) 152.0586, found 152.0586.

[0352] A solution of triphenylphosphine (1.23 g, 4.69 mmol) in methylenechloride (15 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (947 mg, 5.32 mmol). The resulting brown-purplesolution was stirred at 0° C. for 5 min and then treated with3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as inExample 54A, 900 mg, 3.13 mmol). The reaction mixture was stirred at 0°C. and then allowed to warm to 25° C. over 45 min. The reaction mixturewas then treated with 6-aminonicotinic acid methyl ester (620 mg, 4.07mmol) and pyridine (0.38 mL, 4.7 mmol), and the reaction mixture wasallowed to stir at 25° C. for 20 h. The resulting reaction mixture wasdiluted with water (15 mL) and then extracted with methylene chloride(3×15 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid methyl ester (1.10 g, 84%) as a white foam: [α]²³ ₅₈₉=−68.0°(c=0.128, chloroform); FAB-HRMS m/e calcd for C₂₁H₂₂Cl₂N₂O₃ (M+H)⁺421.1086, found 421.1079.

EXAMPLE 466-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid

[0353]

[0354] A solution of3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-propionamide(prepared as in Example 38(B)(b), 50 mg, 0.12 mmol) in ethanol (10 mL)at 25° C. was treated with a solution of potassium hydroxide (20 mg,0.36 mmol) in water (2 mL). The reaction was stirred at 25° C. for 2 h.At this time, the reaction was diluted with water (5 mL). The ethanolwas removed in vacuo. The aqueous layer was then acidified to pH=2 witha 1N aqueous hydrochloric acid solution. This solution was extractedwith methylene chloride (3×10 mL). The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethylacetate with acetic acid) afforded6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid(34 mg, 71%) as white foam: EI-HRMS m/e calcd for C₂₀H₂₀Cl₂N₂O₃ (M⁺)406.0851, found 406.0852.

EXAMPLE 476-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid

[0355]

[0356] A solution of6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester (prepared as in Example 31(B)(c), 62.6 mg, 0.16 mmol) intetrahydrofuran/water/methanol (0.40 mL, 3:1:1) was treated with a 2Naqueous sodium hydroxide solution (0.16 mL, 0.32 mmol). The reaction wasstirred at 25° C. for 24 h. The reaction mixture was then poured intowater and extracted with chloroform (2×30 mL). The aqueous layer wasthen acidified to pH=1 with a 1N aqueous hydrochloric acid solution. Theproduct was extracted into chloroform/methanol (9:1, 3×25 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 75/25 hexanes/ethyl acetate w/acetic acid) afforded6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid(17.0 mg, 31.5%) as a white solid: mp 206-208° C.; EI-HRMS m/e calcd forC₂₀H₂₁ClN₂O₂ (M⁺) 372.1240, found 372.1244.

EXAMPLE 486-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinicacid

[0357]

[0358] A solution of6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinicacid methyl ester (prepared as in Example 53(B)(a), 100 mg, 0.23 mmol)in tetrahydrofuran (500 μL) was treated with a 0.8M aqueous lithiumhydroxide solution (300 μL, 0.23 mmol). The solution was stirred at 25°C. for 4 h. The reaction mixture was then directly purified by columnchromatography. Flash chromatography (Merck Silica gel 60, 230-400 mesh,1/3 methanol/ethyl acetate) afforded6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinicacid (65 mg, 70%) as a white solid: mp 191-193° C.; FAB-HRMS m/e calcdfor C₂₁H₂₄N₂O₅S (M+H)⁺ 417.1484, found 417.1484.

EXAMPLE 493-Cyclopentyl-2(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide

[0359]

[0360] A solution of3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-propionamide(prepared as in Example 38(B)(b), 398 mg, 0.95 mmol) in diethyl ether(30 mL) cooled to 0° C. was treated with lithium aluminum hydride (54mg, 1.4 mmol). This slurry was allowed to slowly warm to 25° C. Thereaction was stirred at 25° C. for 16 h. At this time, the reaction wasquenched with water (10 mL) and extracted with ethyl acetate (3×15 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide(131 mg, 35%) as a white foam: EI-HRMS m/e calcd for C₂₀H₂₂Cl₂N₂O₂ (M⁺)392.1058, found 392.1062.

EXAMPLE 502-(4-Chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide

[0361]

[0362] A solution of6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester (prepared as in Example 31(B)(c), 83.3 mg, 0.21 mmol) intetrahydrofuran (2.1 mL) was added to a cooled (0° C.) slurry of lithiumaluminum hydride (12.0 mg, 0.32 mmol) in tetrahydrofuran (1.54 mL). Thereaction mixture was stirred at 0° C. for 2.5 h. The reaction was thenquenched by the dropwise addition of water (25 mL). The reaction wasfurther diluted with water and was then extracted with ethyl acetate(3×35 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide(12.5 mg, 16.1%) as a white solid: mp 60-62° C.; EI-HRMS m/e calcd forC₂₀H₂₃ClN₂O₂(M⁺) 358.1448, found 358.1443.

EXAMPLE 513-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide

[0363]

[0364] A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionicacid (prepared as in Example 38A, 183 mg, 0.63 mmol) in methylenechloride (6.37 mL) was cooled to 0° C. and then treated with a 2.0Msolution of oxalyl chloride in methylene chloride (0.35 mL, 0.7 mmol)and a few drops of N,N-dimethylformamide. The reaction mixture wasstirred at 0° C. for 10 min and then at 25° C. for 30 min. The reactionmixture was then treated with 5-benzyloxy-pyridin-2-ylamine (281 mg, 1.4mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol). The reactionmixture was stirred at 25° C. for 16 h. At this time, the reaction wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 70/30 hexanes/ethyl acetate) affordedN-(5-benzyloxy-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide(150 mg, 50.0%) as a yellow solid: mp 47-49° C.; EI-HRMS m/e calcd forC₂₆H₂₆Cl₂N₂O₂ (M⁺) 469.1449, found 469.1455.

[0365] A solution ofN-(5-benzyloxy-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide(145.3 mg, 0.3 mmol) in methanol (5.1 mL) was treated with 10% palladiumon activated carbon. The reaction mixture was stirred under hydrogen gasat 25° C. for 16 h. The catalyst was then filtered off through a pad ofcelite, which was washed well with ethyl acetate. The resulting filtratewas concentrated in vacuo to give3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide(92.2 mg, 78.5%) as a tan solid: mp 79-81° C.; EI-HRMS m/e calcd forC₁₉H₂₀Cl₂N₂O₂ (M⁺) 378.0896, found 378.0890.

EXAMPLE 523-Cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide

[0366]

[0367] A solution of6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinicacid methyl ester (prepared as in Example 53(B)(a), 110 mg, 0.26 mmol)in diethyl ether (500 μL) was cooled to 0° C. and then slowly treatedwith lithium aluminum hydride (15 mg, 0.38 mmol). The reaction mixturewas stirred at 0° C. for 30 min then allowed to warm to 25° C. After 1 hat 25° C., thin layer chromatography still indicated the presence of thestarting material. An additional amount of lithium aluminum hydride (10mg, 0.26 mmol) was added to the reaction mixture, and the reactionmixture was allowed to stir at 25° C. for 1 h. The reaction mixture wasthen slowly quenched by the dropwise addition of water (10 mL). Theresulting mixture was partitioned between water and ethyl acetate. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/3 hexanes/ethyl acetate) afforded the3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide(60 mg, 57%) as a yellow foam: mp 74-77° C.; EI-HRMS m/e calcd forC₂₁H₂₆N₂O₄S (M⁺) 402.1613, found 402.1617.

EXAMPLE 533-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide

[0368]

[0369] A solution triphenylphosphine (177 mg, 0.68 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (132 mg, 0.74 mmol) in small portions. The reactionmixture was allowed to warm to 25° C. over 30 min and then was treatedwith 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (preparedas in Example 3A, 200 mg, 0.68 mmol). The reaction mixture was stirredat 25° C. for 30 min and then treated with 2-amino-5-methylpyridine (154mg, 1.42 mmol). The resulting reaction mixture was stirred at 25° C. for1 h. The crude reaction mixture was directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) to afford impure3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamideas a red solid. The impure product was further purified by precipitationfrom 1/1 hexanes/ethyl acetate to afford pure3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide(80 mg, 31%) as an off-white solid: mp 184-185° C.; EI-HRMS m/e calcdfor C₂₁H₂₆N₂O₃S (M⁺) 386.1664, found 386.1664.

[0370] In an analogous manner, there was obtained:

[0371] a) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acidand 6-aminonicotinic acid methyl ester:6-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinicacid methyl ester as a yellow foam: mp 82-85° C.; EI-HRMS m/e calcd forC₂₂H₂₆N₂O₅S (M⁺) 430.1562, found 430.1571.

EXAMPLE 54N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide

[0372]

[0373] A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionicacid (prepared as in Example 38A, 5.00 g, 17.4 mmol) in tetrahydrofuran(150 mL) cooled to −78° C. was treated with triethylamine (2.77 mL, 19.9mmol) followed by trimethylacetyl chloride (2.24 mL, 18.2 mmol). Theresulting white slurry was stirred at −78° C. for 15 min and then at 0°C. for 45 min. In a separate flask, a solution of(S)-4-isopropyl-2-oxazolidinone (2.14 g, 16.57 mmol) in tetrahydrofuran(80 mL) cooled to −78° C. was treated with a 2.0M solution ofn-butyllithium in hexanes (8.7 mL, 17.4 mmol). The solution was stirredat −78° C. for 10 min and then allowed to warm to 25° C. where it wasstirred for an additional 10 min. At this time, the first reactionmixture was recooled to −78° C. The second reaction mixture was added tothe first reaction mixture over a period of 5 min via cannula. Thecombined reaction was then stirred at −78° C. for 15 min and thenallowed to warm to 25° C. where it was stirred for an additional 1.5 h.At this time, the reaction was quenched by the addition of a saturatedaqueous sodium bisulfite solution (50 mL) and extracted with ethylacetate (3×40 mL). The combined organic layers were washed with asaturated aqueous sodium bicarbonate solution (1×20 mL) and a saturatedaqueous sodium chloride solution (1×20 mL), dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded twoproducts: (1)3-[3-cyclopentyl-2(S)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one(2.15 g, 33%) as a clear oil: [α]²³ ₅₈₉=+87.5° (c=0.160, chloroform);EI-HRMS m/e calcd for C₂₀H₂₅Cl₂NO₃ (M⁺) 397.1211, found 397.1215; and(2)3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one(1.88 g, 28%) as a white solid: mp 71.9-74.6° C.; [α]²³ ₅₈₉=−27.6°(c=0.188, chloroform); EI-HRMS m/e calcd for C₂₀H₂₅Cl₂NO₃ (M⁺) 397.1211,found 397.1212.

[0374] A solution of3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one(1.88 g, 4.72 mmol) in tetrahydrofuran (73 mL) and water (22 mL) cooledto 0° C. was treated with a 30% aqueous hydrogen peroxide solution (2.1mL) and lithium hydroxide (394 mg, 9.4 mmol). The reaction was stirredat 0° C. for 1 h. At this time, the reaction was quenched with asaturated aqueous sodium sulfite solution (16 mL) followed by theaddition of a 0.5N aqueous sodium bicarbonate solution (50 mL). Thetetrahydrofuran was then removed in vacuo. The residue was diluted withwater (40 mL) and extracted with methylene chloride (3×20 mL). Theaqueous layer was then acidified to pH=2 with 5N aqueous hydrochloricacid solution and extracted with ethyl acetate (4×25 mL). The combinedorganic layers were then dried over sodium sulfate, filtered, andconcentrated in vacuo to afforded of3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (928 mg, 70%) asa white solid: mp 75.1-78.3° C.; [α]²³ ₅₈₉=−50.30 (c=0.100, chloroform);EI-HRMS m/e calcd for C₁₄H₁₆Cl₂O₂ (M⁺) 286.0527, found 286.0535.

[0375] A solution of triphenylphosphine (344 mg, 1.31 mmol) in methylenechloride (10 mL) cooled to 0° C. was treated with N-bromosuccinimide(263 mg, 1.48 mmol). The reaction solution was stirred at 0° C. for 5min. At this time, 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl) propionicacid (250 mg, 0.87 mmol) was added. The reaction was allowed to slowlywarm to 25° C. over 45 min. At this time, 5-chloro-2-aminopyridine (145mg, 1.13 mmol) and pyridine (0.11 mL, 1.31 mmol) were added to thereaction mixture. The reaction was stirred at 25° C. for 20 h. At thistime, the reaction was diluted with water (10 mL) and extracted withmethylene chloride (3×10 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethylacetate) affordedN-(5-chloro-pyridin-2-yl)3-cyclopentyl-2-(R)-(3,4-dichloro-phenyl)-propionamide(289 mg, 84%) as a white solid: mp 125-128° C.; [α]²³ ₅₈₉=−65.6°(c=0.16, chloroform); EI-HRMS m/e calcd for C₁₉H₁₉Cl₃N₂O (M⁺) 396.0563,found 396.0565.

[0376] In an analogous manner, there were obtained:

[0377] a) From 2-amino pyridine and3-cyclopentyl-2(R)-(3,4-dichloro-phenyl) propionic acid:3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide asa white foam: [α]²³ ₅₈₉=−56.2° (c=0.153, chloroform); EI-HRMS m/e calcdfor C₁₉H₂₀Cl₂N₂O (M⁺) 362.0953, found 362.0952.

[0378] b) From 2-aminothiazole and3-cyclopentyl-2(R)-(3,4-dichloro-phenyl) propionic acid:3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-thiazol-2-yl-propionamide asa white solid: mp 133.4-136.5° C.; [α]²³ ₅₈₉=−66.0° (c=0.106,chloroform); EI-HRMS m/e calcd for C₁₇H₁₈Cl₂N₂OS (M⁺) 368.0517, found368.0519.

[0379] c) From 2-(amino-thiazol-5-yl)-oxo-acetic acid ethyl ester and3-cyclopentyl-2(R)-3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:(2R)-{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-5-yl}-oxo-aceticacid ethyl ester as a light yellow foam: mp 117-120° C.; FAB-HRMS m/ecalcd for C₂₁H₂₂Cl₂N₂O₄S (M+H)⁺ 469.0755, found 469.0753.

[0380] d) From ethyl 2-amino-4-thiazole glyoxylate and3-cyclopentyl-2(R)-3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:(2R)-{2-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester as a white solid: EI-HRMS m/e calcd for C₂₁H₂₂Cl₂N₂O₄S(M⁺) 468.0677, found 468.0677.

EXAMPLE 553-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide

[0381]

[0382] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(prepared as in Example 38A, 200 mg, 0.70 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(310 mg, 0.70 mmol), N,N-diisopropylethylamine (244 μL, 1.40 mmol), and2-aminoimidazole sulfate (140 mg, 1.05 mmol) in dryN,N-dimethylformamide (5 mL) was stirred at 25° C. under nitrogen for 15h. The reaction mixture was partitioned between water and ethyl acetate.The organic layer was washed sequentially with a 1N aqueous hydrochloricacid solution, water, and a saturated aqueous sodium chloride solution.The organic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide(81.4 mg, 33%) as a white solid: mp 58-60° C.; EI-HRMS m/e calcd forC₁₇H₁₉Cl₂N₃O (M⁺) 351.0905, found 351.0901.

EXAMPLE 563-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionamide

[0383]

[0384] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(prepared as in Example 38A, 70.7 mg, 0.25 mmol) in oxalyl chloride (215μL, 2.46 mmol) was cooled to 0° C. and then treated with 1 drop of dryN,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 30min and then stirred at 25° C. for 3 h. The reaction mixture wasconcentrated in vacuo to afford a yellow oil. This yellow oil wasdissolved in a small amount of methylene chloride and then slowly addedto a solution of 3-amino-5-methylisoxazole (48.3 mg, 0.49 mmol) andtriethylamine (68 mL, 0.49 mmol) in methylene chloride (1.2 mL). Theresulting reaction mixture was stirred at 25° C. for 14 h. The reactionmixture was concentrated in vacuo to remove methylene chloride. Theresulting residue was diluted with ethyl acetate (100 mL) and thenwashed with a 10% aqueous hydrochloric acid solution. The organic layerwas dried over sodium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionamide(78.3 mg, 87%) as a yellow glass: mp 84-86° C.; FAB-HRMS m/e calcd forC₁₈H₂₀Cl₂N₂O₂ (M+H)⁺ 367.0981, found 367.0982.

EXAMPLE 573-Cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide

[0385]

[0386] A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (102 mg, 0.23 mmol),3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as inExample 38A, 60 mg, 0.21 mmol), N,N-diisopropylethylamine (73 μL, 0.42mmol), and 2-aminooxazole (27 mg, 0.31 mmol) in dryN,N-dimethylformamide (1 mL) was stirred at 25° C. under nitrogen for 15h. The reaction mixture was partitioned between water and ethyl acetate.The organic layer was washed sequentially with a 1N aqueous hydrochloricacid solution, water, and a saturated aqueous sodium chloride solution.The organic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide (34.9mg, 47%) as a white solid: mp 134-136° C.; EI-HRMS m/e calcd forC₁₇H₁₈Cl₂N₂O₂(M⁺) 352.0745, found 352.0750.

EXAMPLE 583-Cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide

[0387]

[0388] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(prepared as in Example 38A, 625.2 mg, 2.18 mmol),O-benzotriazol-l-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(908.3 mg, 2.39 mmol), N,N-diisopropylethylamine (1.1 mL, 6.53 mmol),and 3-aminopyridazine (310.6 mg, 3.27 mmol) in dry N,N-dimethylformamide(11 mL) was stirred at 25° C. under nitrogen for 72 h. The reactionmixture was concentrated in vacuo to remove N,N-dimethylformamide. Theresulting residue was diluted with ethyl acetate (200 mL). The organiclayer was washed with a 10% aqueous hydrochloric acid solution and asaturated aqueous sodium chloride solution. The organic layer was driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide(493.8 mg, 62%) as a white foam: mp 70-71° C.; EI-HRMS m/e calcd forC₁₈H₁₉Cl₂N₃O (M⁺) 363.0905, found 363.0908.

EXAMPLE 593-Cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide

[0389]

[0390] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(prepared as in Example 38A, 100 mg, 0.35 mmol) in methylene chloride (1mL) was treated with 2 drops of dry N,N-dimethylformamide. The reactionmixture was cooled to 0° C. and then treated dropwise with oxalylchloride (34 mL, 0.39 mmol). The reaction mixture was stirred at 0° C.for 10 min and then stirred at 25° C. for 2 h. The reaction mixture wasconcentrated in vacuo. The resulting residue was dissolved in a smallamount of methylene chloride and was slowly added to a cooled (0° C.)solution of 2-aminopyrimidine (67 mg, 0.70 mmol) in methylene chloride(1 mL). The resulting reaction mixture was stirred at 0° C. for 30 minand then stirred at 25° C. for 2 h. The reaction mixture wasconcentrated in vacuo to remove methylene chloride. The resultingresidue was diluted with water and extracted with ethyl acetate (3×50mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution. The organic layer was dried over magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide (85.4mg, 67%) as a white solid: mp 103-105° C.; EI-HRMS m/e calcd forC₁₈H₁₉Cl₂N₃O (M⁺) 363.0905, found 363.0915.

EXAMPLE 60 3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrimidine-4-yl-propionamide

[0391]

[0392] A solution of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionicacid (prepared as in Example 54A, 200 mg, 0.69 mmol) in methylenechloride (5 mL) was treated with 1 drop of N,N-dimethylformamide andthen cooled to 0° C. The reaction mixture was then treated with a 2.0Msolution of oxalyl chloride in methylene chloride (0.52 mL, 1.04 mmol).The reaction mixture was stirred at 0° C. for 30 min and then treatedwith a solution of 4-aminopyrimidine (131 mg, 1.38 mmol) intetrahydrofuran (10 mL) and pyridine (0.28 mL, 3.45 mmol). The resultingreaction mixture was stirred at 23° C. for 14 h. The reaction mixturewas then diluted with water (10 mL) and extracted with methylenechloride (3×15 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 3/2 hexanes/ethyl acetate) afforded3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrimidin-4-yl-propionamide(147 mg, 60%) as a white solid: mp 166.5-169.3° C.; EI-HRMS m/e calcdfor C₁₈H₁₉Cl₂N₃O (M⁺) 363.0905, found 363.0909.

EXAMPLE 613-Cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide

[0393]

[0394] A solution of diisopropylamine (3.2 mL, 23.16 mmol) in drytetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooledto −78° C. under nitrogen and then treated with a 10M solution ofn-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) indry tetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). Thereaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas then stirred at −78° C. for 30 min and then allowed to warm to 25°C. where it was stirred for 24 h. The reaction mixture was quenched withwater and then concentrated in vacuo to remove tetrahydrofuran. Theremaining aqueous phase was acidified to pH=2 with a 10% aqueoushydrochloric acid solution and then extracted with ethyl acetate (1×200mL). The organic layer was washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) asa cream solid: mp 91-93° C.; EI-HRMS m/e calcd for C₁₅H₂₀O₂S (M⁺)264.1184, found 264.1177.

[0395] A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionicacid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) inmethylene chloride (2 mL) was cooled to 0° C. and then slowly treatedwith N-bromosuccinimide (150 mg, 0.84 mmol). After the complete additionof N-bromosuccinimide, the reaction mixture was allowed to warm to 25°C. over 30 min. The reaction mixture was then treated with2-aminothiazole (160 mg, 1.60 mmol), and the resulting reaction mixturewas stirred at 25° C. for 15 h. The reaction mixture was thenconcentrated in vacuo to remove methylene chloride. The remainingresidue was diluted with water and ethyl acetate. The organic layer waswashed sequentially with a 1N aqueous hydrochloric acid solution and asaturated aqueous sodium bicarbonate solution, dried over magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) affordedcrude3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide asa yellow solid. Recrystallization from 3/1 hexanes/ethyl acetateafforded pure3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide(114 mg, 44%) as a white solid: mp 195-196° C.; EI-HRMS m/e calcd forC₁₈H₂₂N₂OS₂ (M⁺) 346.1174, found 346.1171.

[0396] A solution3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide(75 mg, 0.216 mmol) in methylene chloride (1 mL) was treated with3-chloroperoxybenzoic acid (75% grade, 50 mg, 0.216 mmol). The reactionmixture was immediately monitored by thin layer chromatography, and theresults indicated the immediate absence of starting material. Thereaction mixture was partitioned between water and methylene chlorideand then washed with a saturated aqueous sodium bicarbonate solution.The organic layer was further washed with water and then dried overmagnesium sulfate, filtered, and concentrated in vacuo.Recrystallization from 1/1 hexanes/ethyl acetate afforded3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide(25 mg, 32%) as a white solid: mp 170-173° C.; EI-HRMS m/e calcd forC₁₈H₂₂N₂O₂S₂ (M⁺) 362.1123, found 362.1121.

EXAMPLE 62{2-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester

[0397]

[0398] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in drytetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooledto −78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00mmol) in dry tetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). Thereaction mixture was allowed to stir at −78° C. for 55 min, at whichtime, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to 25° C. where it was stirred for 41 h. Thereaction mixture was quenched with water and then concentrated in vacuoto remove tetrahydrofuran. The remaining aqueous phase was acidified topH=2 with a 10% aqueous hydrochloric acid solution and then extractedwith ethyl acetate (1×300 mL). The organic layer was washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₂S (M⁺) 318.0901, found 318.0912.

[0399] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops ofconcentrated sulfuric acid. The resulting reaction mixture was heatedunder reflux for 36 h. The reaction mixture was allowed to cool to 25°C. and then concentrated in vacuo to remove methanol. The residue wasdiluted with ethyl acetate (200 mL). The organic phase was washed with asaturated aqueous sodium bicarbonate solution (1×100 mL) and a saturatedaqueous sodium chloride solution (1×100 mL), dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 70-230 mesh, 97/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1052.

[0400] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.14 g, 3.43 mmol) in methylene chloride (8.6 mL) was treatedwith 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g based on 80%, 9.26mmol). The reaction mixture was stirred at 25° C. for 17 h, at whichtime, thin layer chromatography showed the presence of two new lower Rproducts. An additional 2.00 g of 3-chloroperoxybenzoic acid was addedto the reaction mixture to drive the conversion of the sulfoxide to thesulfone, and the resulting reaction mixture was stirred at 25° C. for 3d. The reaction mixture was concentrated in vacuo to remove methylenechloride. The resulting residue was diluted with ethyl acetate (300 mL).The organic phase was washed with a saturated aqueous sodium bicarbonatesolution (3×100 mL) and a saturated aqueous sodium chloride solution(1×100 mL), dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (1.19 g, 95%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₄S (M⁺) 364.0956, found 364.0965.

[0401] A solution of3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was treated witha 0.8M aqueous lithium hydroxide solution (3.6 mL, 2.92 mmol). Thereaction mixture was stirred at 25° C. for 23 h and then concentrated invacuo to remove tetrahydrofuran. The remaining aqueous layer wasacidified to pH=2 with a 10% aqueous hydrochloric acid solution and thenextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with a saturated aqueous sodium chloride solution (1×100mL), dried over sodium sulfate, filtered, and concentrated in vacuo toafford a cream solid. This solid was purified by triturating withdiethyl ether/petroleum ether to provide pure3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (527.0mg, 77%) as a white solid: mp 143-145° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₄S (M⁺) 350.0800, found 350.0816.

[0402] A solution of triphenylphosphine (97 mg, 0.371 mmol) in methylenechloride (1.5 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (66 mg, 0.371 mmol). The reaction mixture was stirredat 0° C. for 20 min and then treated with3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (100mg, 0.285 mmol). The resulting reaction mixture was stirred at 0° C. for10 min, allowed to warm to 25° C., and then treated with ethyl2-amino-4-thiazoleacetate (123 mg, 0.657 mmol). The resulting reactionmixture was stirred at 25° C. for 3 d. The reaction mixture was thenconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 3/1 hexanes/ethyl acetate) afforded{2-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl-amino]-thiazol-4-yl}-aceticacid ethyl ester (107 mg, 72%) as a yellow foam: mp 48-51° C.; EI-HRMSm/e calcd for C₂₂H₂₅F₃N₂O₅S₂ (M⁺) 518.1157, found 518.1157.

EXAMPLE 63N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide

[0403]

[0404] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in drytetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooledto −78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00mmol) in dry tetrahydrofuran (7.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). Thereaction mixture was allowed to stir at −78° C. for 55 min, at whichtime, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to 25° C. where it was stirred for 41 h. Thereaction mixture was quenched with water and then concentrated in vacuoto remove tetrahydrofuran. The remaining aqueous phase was acidified topH=2 with a 10% aqueous hydrochloric acid solution and then extractedwith ethyl acetate (1×300 mL). The organic layer was washed with asaturated aqueous sodium chloride solution (1×100 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47g, 58%) as a cream solid: mp 69-71° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₂S (M⁺) 318.0901, found 318.0912.

[0405] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops ofconcentrated sulfuric acid. The resulting reaction mixture was heatedunder reflux for 36 h. The reaction mixture was allowed to cool to 25°C. and then concentrated in vacuo to remove methanol. The residue wasdiluted with ethyl acetate (200 mL). The organic phase was washed with asaturated aqueous sodium bicarbonate solution (1×100 mL) and a saturatedaqueous sodium chloride solution (1×100 mL), dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 70-230 mesh, 97/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1052.

[0406] A solution of3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methylester (1.14 g, 3.43 mmol) in methylene chloride (8.6 mL) was treatedwith 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g based on 80%, 9.26mmol). The reaction mixture was stirred at 25° C. for 17 h, at whichtime, thin layer chromatography showed the presence of two new lowerR_(f) products. An additional 2.00 g of 3-chloroperoxybenzoic acid wasadded to the reaction mixture to drive the conversion of the sulfoxideto the sulfone, and the resulting reaction mixture was stirred at 25° C.for 3 d. The reaction mixture was concentrated in vacuo to removemethylene chloride. The resulting residue was diluted with ethyl acetate(300 mL). The organic phase was washed with a saturated aqueous sodiumbicarbonate solution (3×100 mL) and a saturated aqueous sodium chloridesolution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 19/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (1.19 g, 95%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₄S (M⁺) 364.0956, found 364.0965.

[0407] A solution of3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methylester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was treated witha 0.8M aqueous lithium hydroxide solution (3.6 mL, 2.92 mmol). Thereaction mixture was stirred at 25° C. for 23 h and then concentrated invacuo to remove tetrahydrofuran. The remaining aqueous layer wasacidified to pH=2 with a 10% aqueous hydrochloric acid solution and thenextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with a saturated aqueous sodium chloride solution (1×100mL), dried over sodium sulfate, filtered, and concentrated in vacuo toafford a cream solid. This solid was purified by triturating withdiethyl ether/petroleum ether to provide pure3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (527.0mg, 77%) as a white solid: mp 143-145° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₄S (M⁺) 350.0800, found 350.0816.

[0408] A solution of triphenylphosphine (206 mg, 0.785 mmol) inmethylene chloride (4 mL) was cooled to 0° C. and then slowly treatedwith N-bromosuccinimide (140 mg, 0.785 mmol). The reaction mixture wasstirred at 0° C. for 10 min and then treated with3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (250mg, 0.710 mmol). The resulting reaction mixture was stirred at 0° C. for10 min and then allowed to warm to 25° C. where it was stirred for 30min. The reaction mixture was then treated with 2-amino-5-bromopyridine(271 mg, 1.57 mmol). The resulting reaction mixture was stirred at 25°C. for 15 h. The reaction mixture was then concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethylacetate) afforded the pureN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide(226 mg, 63%) as a yellow foam: mp 130-132° C.; EI-HRMS m/e calcd forC₂₀H₂₀BrF₃N₂O₃S (M⁺) 504.0330, found 504.0325.

EXAMPLE 642-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0409]

[0410] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32 mmol)in methanol (40 mL) was treated with Amberlyst® 15 ion exchange resin(15.00 g). The resulting reaction mixture was heated under reflux for 64h. The reaction mixture was allowed to cool to 25° C. and then filteredto remove the Amberlyst® 15 ion exchange resin. The filtrate wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 3/1 hexanes/ethyl acetate) afforded4-chloro-3-nitro-phenylacetic acid methyl ester (1.91 g, 89%) as ayellow oil: EI-HRMS m/e calcd for C₉H₈ClNO₄ (M⁺) 229.0142, found229.0146.

[0411] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in drytetrahydrofuran (45 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) was cooled to−78° C. and then treated dropwise with a 2.5M solution of n-butyllithiumin hexanes (9.56 mL, 23.9 mmol) over a 10 min period. The pale yellowreaction mixture was stirred at −78° C. for 20 min and then slowlytreated with a solution of 4-chloro-3-nitrophenylacetic acid methylester (5.00 g, 21.8 mmol) in a small amount of tetrahydrofuran over a 15min period. The reaction mixture turned deep purple (almost black) incolor. The reaction mixture was then stirred at −78° C. for 1 h, atwhich time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was then stirred at −78° C. and then allowed to warm to 25° C.,where it was stirred for 48 h. The reaction mixture was quenched with asaturated aqueous ammonium chloride solution (50 mL), and the resultingreaction mixture was concentrated in vacuo to remove tetrahydrofuran.The remaining residue was diluted with ethyl acetate (150 mL) and water(50 mL). The organic phase was washed with a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 hexanes/ethyl acetate) afforded2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid methyl ester(2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for C₁₅H₁₈ClNO₄ (M⁺)311.0924, found 311.0927.

[0412] A solution of 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionicacid methyl ester (260 mg, 0.834 mmol) in tetrahydrofuran (3 mL) wastreated with a 0.8M aqueous lithium hydroxide solution (1.25 mL, 1.00mmol). The reaction mixture was stirred at 25° C. for 15 h. Theresulting reaction mixture was partitioned between water (50 mL) andethyl acetate (50 mL) and then treated with a 1N aqueous hydrochloricacid solution (10 mL). The layers were shaken and separated. The aqueouslayer was further extracted with ethyl acetate (50 mL). The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (243 mg, 98%)as a yellow solid which was used without further purification: mp112-115° C.; FAB-HRMS m/e calcd for C₁₄H₁₆ClNO₄ (M+H)⁺298.0847, found298.0851.

[0413] A solution of triphenylphosphine (105 mg, 0.403 mmol) inmethylene chloride (1 mL) was cooled to 0° C. and then slowly treatedwith N-bromosuccinimide (72 mg, 0.403 mmol). The reaction mixture wasstirred at 0° C. for 20 min and then treated with2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.336mmol). The resulting reaction mixture was stirred at 0° C. for 10 minand then allowed to warm to 25° C. where it was stirred for 20 min. Thereaction mixture was then treated with 2-aminothiazole (74 mg, 0.739mmol). The resulting reaction mixture was stirred at 25° C. for 15 h.The crude reaction mixture was treated with a solution of hexanes/ethylacetate (2 mL, 3:1) and then directly purified by flash chromatography(Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate). The pure2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(93 mg, 73%) was obtained as a pale yellow foam: mp 68-72° C. (foam togel); EI-HRMS m/e calcd for C₁₇H₁₈ClN₃O₃S (M⁺) 379.0757, found 379.0760.

EXAMPLE 652-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0414]

[0415] A solution of triphenylphosphine (105 mg, 0.403 mmol) inmethylene chloride (1 mL) was cooled to 0° C. and then slowly treatedwith N-bromosuccinimide (72 mg, 0.403 mmol). The reaction mixture wasstirred at 0° C. for 20 min and then treated with2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (prepared as inExample 64, 100 mg, 0.336 mmol). The resulting reaction mixture wasstirred at 0° C. for 10 min and then allowed to warm to 25° C. where itwas stirred for 20 min. The reaction mixture was then treated with2-aminopyridine (70 mg, 0.739 mmol). The resulting reaction mixture wasstirred at 25° C. for 15 h. The crude reaction mixture was treated witha solution of hexanes/ethyl acetate (2 mL, 3:1) and then directlypurified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1hexanes/ethyl acetate). The pure2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide(60 mg, 48%) was obtained as a pale yellow foam: mp 48-52° C. (foam togel); EI-HRMS m/e calcd for C₁₉H₂₀ClN₃O₃ (M⁺) 373.1193, found 373.1185.

EXAMPLE 66N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide

[0416]

[0417] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32 mmol)in methanol (40 mL) was treated with Amberlyst® 15 ion exchange resin(15.00 g). The resulting reaction mixture was heated under reflux for 64h. The reaction mixture was allowed to cool to 25° C. and then filteredto remove the Amberlyst® 15 ion exchange resin. The filtrate wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 3/1 hexanes/ethyl acetate) afforded4-chloro-3-nitrophenylacetic acid methyl ester (1.91 g, 89%) as a yellowoil: EI-HRMS m/e calcd for C₉H₈ClNO₄ (M⁺) 229.0142, found 229.0146.

[0418] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in drytetrahydrofuran (45 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) was cooled to−78° C. and then treated dropwise with a 2.5M solution of n-butyllithiumin hexanes (9.56 mL, 23.9 mmol) over a 10 min period. The pale yellowreaction mixture was stirred at −78° C. for 20 min and then slowlytreated with a solution of 4-chloro-3-nitrophenylacetic acid methylester (5.00 g, 21.8 mmol) in a small amount of tetrahydrofuran over a 15min period. The reaction mixture turned deep purple (almost black) incolor. The reaction mixture was then stirred at −78° C. for 1 h, atwhich time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol) in asmall amount of dry tetrahydrofuran was added dropwise. The reactionmixture was then stirred at −78° C. and then allowed to warm to 25° C.where it was stirred for 48 h. The reaction mixture was quenched with asaturated aqueous ammonium chloride solution (50 mL), and the resultingreaction mixture was concentrated in vacuo to remove tetrahydrofuran.The remaining residue was diluted with ethyl acetate (150 mL) and water(50 mL). The organic phase was washed with a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 4/1 hexanes/ethyl acetate) afforded2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl ester(2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for C₁₅H₁₈ClNO₄ (M⁺)311.0924, found 311.0927.

[0419] A solution of 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionicacid methyl ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36g, 3.53 mmol) in dimethyl sulfoxide (3 mL) was heated at 130° C. for 5h. The black reaction mixture was then poured over ice (20 g), resultingin the formation of a brown sticky substance. The resulting mixture wasthen treated with ethyl acetate (50 mL) and water (50 mL), and thelayers were separated. The aqueous layer was further extracted withethyl acetate (2×50 mL). The combined organic layers were washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methylester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for C₁₆H₂₁NO₆S(M+H)⁺356.1169, found 356.1175.

[0420] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methylester (1.17 g, 3.29 mmol) in tetrahydrofuran (6 mL) was treated with a0.8M aqueous lithium hydroxide solution (6.17 mL, 4.94 mmol). Thereaction mixture was stirred at 25° C. for 3 h. The reaction mixture wasthen diluted with water (50 mL), a 1N aqueous hydrochloric acid solution(10 mL), and ethyl acetate (50 mL). The layers were separated, and theaqueous layer was back-extracted with ethyl acetate (2×50 mL). Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (993mg, 88%) as a yellow foam which contained a small impurity. A smallamount of the yellow foam (50 mg) was re-purified using Biotagechromatography (FLASH 40S, Silica, 3/1 then 1/1 hexanes/ethyl acetate)to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionicacid as a white foam: mp 114-118° C. (foam to gel); FAB-HRMS m/e calcdfor C₁₅H₁₉NO₆S (M+H)⁺342.1011, found 342.1014.

[0421] A solution of triphenylphosphine (212 mg, 0.81 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (144 mg, 0.81 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (250mg, 0.73 mmol). The resulting reaction mixture was stirred at 0° C. for5 min and then allowed to warm to 25° C. where it was stirred for 30min. The reaction mixture was then treated with 2-amino-5-bromopyridine(279 mg, 1.61 mmol). The resulting reaction mixture was stirred at 25°C. for 15 h. The crude reaction mixture was directly purified by flashchromatography, (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethylacetate), to affordN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide(121 mg, 33%) as a white foam: mp 80-83° C. (foam to gel); FAB-HRMS m/ecalcd for C₂₀H₂₂BrN₃O₅S (M+H)⁺496.0542, found 496.0543.

EXAMPLE 673-Cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0422]

[0423] A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylenechloride (2 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (94 mg, 0.53 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid(prepared as in Example 66, 150 mg, 0.44 mmol). The resulting reactionmixture was stirred at 0° C. for 5 min and then allowed to warm to 25°C. where it was stirred for 25 min. The reaction mixture was thentreated with 2-aminothiazole (97 mg, 0.97 mmol). The resulting reactionmixture was stirred at 25° C. for 15 h. The crude reaction mixture wasdirectly purified by flash chromatography, (Merck Silica gel 60, 230-400mesh, 1/1 hexanes/ethyl acetate), to afford3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide(96 mg, 52%) as a pale yellow solid: mp 121-124° C.; FAB-HRMS m/e calcdfor C₁₈H₂₁N₃O₅S₂ (M+H)⁺424.1001, found 424.1000.

[0424] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide(150 mg, 0.354 mmol) in methanol (3 mL) was treated with 10% palladiumon activated carbon (50 mg). The reaction mixture was stirred under apositive pressure of hydrogen gas (balloon) at 25° C. and atmosphericpressure for 3 h. The catalyst was then filtered off through a pad ofcelite, and the celite pad was washed well with ethyl acetate. Thefiltrate was concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 20/1 methylene chloride/methanol) afforded3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(85 mg, 59%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd forC₁₈H₂₃N₃O₄S₂ (M⁺) 409.1130, found 409.1131.

EXAMPLE 682-(3-Amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0425]

[0426] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide(prepared as in Example 67, 100 mg, 0.236 mmol) in methanol (2 mL) wastreated with a solution of ammonium chloride (27 mg, 0.500 mmol) inwater (200 μL). The reaction mixture was then treated with zinc dust(151 mg, 2.31 mmol). The reaction mixture was heated under reflux for 2h. The reaction mixture was allowed to cool to 25° C. and then filteredthrough a pad of celite. The celite pad was washed well with methanol.The filtrate was concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(40 mg, 43%) as a white solid: mp 207-209° C.; EI-HRMS m/e calcd forC₁₈H₂₃N₃O₃S₂ (M⁺) 393.1181, found 393.1180.

EXAMPLE 693-Cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propionamide

[0427]

[0428] A solution of 3-(trifluoromethylthio)phenylacetic acid (5.00 g,21.17 mmol) in methanol (50 mL) was treated slowly with 10 drops ofconcentrated sulfuric acid. The resulting reaction mixture was heatedunder reflux for 18 h. The reaction mixture was allowed to cool to 25°C. and then concentrated in vacuo to remove methanol. The residue wasdiluted with ethyl acetate (100 mL). The organic phase was washed with asaturated aqueous sodium bicarbonate solution (1×100 mL), dried overmagnesium sulfate, and filtered. The filtrate was concentrated in vacuoto afford (3-trifluoromethylsulfanyl-phenyl)-acetic acid methyl ester(5.28 g, 99%) as a pale yellow oil which was used without furtherpurification: EI-HRMS m/e calcd for C₁₀H₉F₃O₂S (M⁺) 250.0275, found250.0274.

[0429] A solution of diisopropylamine (1.5 mL, 10.5 mmol) in drytetrahydrofuran (27 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to−78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (4.2 mL, 10.5 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of (3-trifluoromethylsulfanyl-phenyl)-acetic acid methylester (2.50 g, 10.0 mmol) in a small amount of tetrahydrofuran. Thereaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (2.10 g, 10.0 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas allowed to warm to 25° C. where it was stirred for 15 h. Thereaction mixture was quenched with water (50 mL) and then partitionedbetween water (75 mL) and ethyl acetate (75 mL). The layers were shakenand separated. The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 8/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-trifluoromethylsulfanyl-phenyl)-propionic acid methylester (2.95 g, 89%) as a colorless oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1047.

[0430] A solution of3-cyclopentyl-2-(3-trifluoromethylsulfanyl-phenyl)-propionic acid methylester (2.75 g, 8.27 mmol) in methylene chloride (30 mL) was treated with3-chloroperoxybenzoic acid (80-85% grade, 4.28 g based on 80%, 20.67mmol). The reaction mixture was stirred at 25° C. for 6 h, at whichtime, thin layer chromatography showed the presence of two new lowerR_(f) products. An additional 4.00 g of 3-chloroperoxybenzoic acid wasadded to the reaction mixture to drive the conversion of the sulfoxideto the sulfone, and the resulting reaction mixture was stirred at 40° C.for 3 d. The reaction mixture was allowed to cool to 25° C. and thenpartitioned between water (100 mL) and methylene chloride (100 mL). Thelayers were shaken and separated. The organic phase was washed twicewith a saturated aqueous sodium bicarbonate solution, washed with water,dried over magnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/methylenechloride) afforded3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acidmethyl ester (2.07 g, 69%) as a colorless oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₄S (M⁺) 364.0956, found 364.0947.

[0431] A solution of3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acidmethyl ester (1.28 g, 3.52 mmol) in tetrahydrofuran (12 mL) was treatedwith a 0.8M aqueous lithium hydroxide solution (4.9 mL, 3.88 mmol). Thereaction mixture was stirred at 25° C. for 24 h and then concentrated invacuo to remove tetrahydrofuran. The resulting yellow oil waspartitioned between water (50 mL) and ethyl acetate (50 mL) and thentreated with a 1N aqueous hydrochloric acid solution. The organic layerwas dried over magnesium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid (1.09g, 99%) as a viscous yellow oil that solidified upon sitting to a whitesolid: mp 86-88° C.; EI-HRMS m/e calcd for C₁₅H₁₇F₃O₄S (M⁺) 350.0800,found 350.0792.

[0432] A solution of triphenylphosphine (194 mg, 0.74 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (132 mg, 0.74 mmol). The reaction mixture was stirredat 0° C. for 15 min and then treated with3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid (200mg, 0.57 mmol). The resulting reaction mixture was stirred at 0° C. for5 min and then allowed to warm to 25° C. over 30 min. The reactionmixture was then treated with 2-aminothiazole (143 mg, 1.43 mmol). Theresulting reaction mixture was stirred at 25° C. for 15 h. The crudereaction mixture was then directly purified by flash chromatography(Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to affordpure3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propionamide(178 mg, 72%) as a light yellow foam: mp 61-64° C. (foam to gel);EI-HRMS m/e calcd for C₁₈H₁₉F₃N₂O₃S₂ (M⁺) 432.0789, found 432.0790.

EXAMPLE 703-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide

[0433]

[0434] A solution of 3-fluoro-4-(trifluoromethyl)phenylacetic acid (2.50g, 11.25 mmol) in methanol (25 mL) was treated slowly with 4 drops ofconcentrated sulfuric acid. The resulting reaction mixture was heatedunder reflux for 15 h. The reaction mixture was allowed to cool to 25°C. and then concentrated in vacuo to remove methanol. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) afforded (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methylester (2.58 g, 97%) as a colorless oil: EI-HRMS m/e calcd for C₁₀H₈F₄O₂(M⁺) 236.0460, found 236.0457.

[0435] A solution of diisopropylamine (1.5 mL, 10.67 mmol) in drytetrahydrofuran (24 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to−78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (4.3 mL, 10.67 mmol). The resulting reactionmixture was stirred at −78° C. for 45 min and then treated dropwise witha solution of (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methylester (2.40 g, 10.16 mmol) in a small amount of tetrahydrofuran. Thereaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (2.24 g, 10.67 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas allowed to warm to 25° C. where it was stirred for 15 h. Thereaction mixture was quenched with a saturated aqueous ammonium chloridesolution (10 mL) and then partitioned between water (75 mL) and ethylacetate (75 mL). The layers were shaken and separated. The aqueous layerwas further extracted with ethyl acetate (1×75 mL). The combined organiclayers were washed with a saturated aqueous sodium chloride solution,dried over magnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 5/1 hexanes/ethylacetate) afforded3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acidmethyl ester (2.69 g, 83%) as a colorless oil: EI-HRMS m/e calcd forC₁₆H₁₈F₄O₂ (M⁺) 318.1243, found 318.1250.

[0436] A solution of3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acidmethyl ester (1.80 g, 5.69 mmol) in tetrahydrofuran (15 mL) was treatedwith a 0.8M aqueous lithium hydroxide solution (7.1 mL, 5.69 mmol). Thereaction mixture was stirred at 25° C. for 15 h. The reaction mixturewas concentrated in vacuo. The resulting residue was diluted with ethylacetate (100 mL) and then washed with a 5% aqueous hydrochloric acidsolution and a saturated aqueous sodium chloride solution. The organiclayer was dried over magnesium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (1.11g, 64%) as a white solid: mp 93-95° C.; FAB-HRMS m/e calcd forC₁₅H₁₆F₄O₂ (M+H)⁺305.1165, found 305.1175.

[0437] A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylenechloride (5 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (300mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for15 min and then allowed to warm to 25° C. where it was stirred for 30min. The reaction mixture was then treated with 2-aminothiazole (218 mg,2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3d. The crude reaction mixture was then directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethylacetate) to afford3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide(243 mg, 64%) as a white solid: mp 194-195° C.; EI-HRMS m/e calcd forC₁₈H₁₈F₄N₂OS (M⁺) 386.1076, found 386.1076.

EXAMPLE 713-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide

[0438]

[0439] A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylenechloride (5 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid(prepared as in Example 70, 300 mg, 0.99 mmol). The resulting reactionmixture was stirred at 0° C. for 15 min and then allowed to warm to 25°C. where it was stirred for 30 min. The reaction mixture was thentreated with 2-aminopyridine (205 mg, 2.18 mmol). The resulting reactionmixture was stirred at 25° C. for 3 d. The crude reaction mixture wasthen directly purified by flash chromatography (Merck Silica gel 60,230-400 mesh, 2/1 hexanes/ethyl acetate) to afford3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide(171 mg, 45%) as a pale yellow foam: mp 40-44° C. (foam to gel); EI-HRMSm/e calcd for C₂₀H₂₀F₄N₂O (M⁺) 380.1512, found 380.1519.

EXAMPLE 722-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0440]

[0441] A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38mmol) in methanol (291 mL) was treated slowly with concentrated sulfuricacid (3 mL). The resulting reaction mixture was heated under reflux for3 d. The reaction mixture was allowed to cool to 25° C. and thenconcentrated in vacuo to remove methanol. The resulting residue wasdiluted with diethyl ether (600 mL). The organic layer was washed with asaturated aqueous sodium bicarbonate solution (3×300 mL) and a saturatedaqueous sodium chloride solution (1×300 mL). The organic layer was driedover sodium sulfate, filtered, and concentrated in vacuo to afford(4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as ayellow liquid which was used without further purification: EI-HRMS m/ecalcd for C₁₀H₁₂O₂S (M⁺) 196.0558, found 196.0559.

[0442] A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl ester(5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was slowly treatedwith bromine (1.74 mL, 33.84 mmol). The reaction mixture was stirred at25° C. for 4 h, at which time, thin layer chromatography still indicatedthe presence of a substantial amount of starting material. The reactionmixture was treated with more bromine (1.74 mL, 33.84 mmol). Thereaction mixture was stirred an additional 4 h at 25° C. and thenquenched with a 10% aqueous sodium bisulfite solution (150 mL). Thereaction mixture was concentrated in vacuo to remove carbontetrachloride. The resulting aqueous layer was extracted with ethylacetate (3×150 mL). The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded(3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 85%)as a light yellow oil: EI-HRMS m/e calcd for C₁₀H₁₁BrO₂S (M⁺) 273.9663,found 273.9661.

[0443] A solution of diisopropylamine (3.4 mL, 24.38 mmol) in drytetrahydrofuran (21 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL) was cooled to−78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (9.8 mL, 24.38 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester(6.10 g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The resultingreaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (5.59 g, 26.60 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas allowed to warm to 25° C. where it was stirred for 15 h. Thereaction mixture was quenched with water (300 mL) and then concentratedin vacuo to remove tetrahydrofuran. The remaining aqueous phase wasextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with a saturated aqueous sodium chloride solution (1×200mL), dried over sodium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1hexanes/ethyl acetate) afforded2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methylester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₂₁BrO₂S (M⁺) 356.0446, found 356.0435.

[0444] A solution of2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methylester (1.07 g, 2.99 mmol) in methylene chloride (15 mL) was treated with3-chloroperoxybenzoic acid (57-86% grade, 1.81 g based on 57%, 5.99mmol). The reaction mixture was stirred at 25° C. for 3 h. The reactionmixture was concentrated in vacuo to remove methylene chloride. Theresulting residue was diluted with diethyl ether (300 mL). The organicphase was washed with a saturated aqueous sodium bicarbonate solution(3×200 mL) and a saturated aqueous sodium chloride solution (1×100 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethylacetate) afforded2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (1.09 g, 94%) as a colorless oil: EI-HRMS m/e calcd forC₁₆H₁₉BrO₄S (M⁺) 388.0344, found 388.0343.

[0445] A solution of2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (1.62 g, 4.16 mol) in methanol (10 mL) was treated with a 1Naqueous sodium hydroxide solution (8.7 mL, 8.74 mol). The reactionmixture was stirred at 25° C. for 27 h. The reaction mixture wasconcentrated in vacuo to remove methanol. The resulting aqueous residuewas acidified to pH=2 with a 10% aqueous hydrochloric acid solution andthen extracted with ethyl acetate (1×400 mL). The organic layer waswashed with water (1×300 mL) and a saturated aqueous sodium chloridesolution (1×300 mL). The organic layer was then dried over sodiumsulfate, filtered, and concentrated in vacuo to afford2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.39g, 89%) as a white solid which was used without further purification: mp149-150° C.; FAB-HRMS m/e calcd for C₁₅H₁₉BrO₄S (M+H)⁺375.0266, found375.0274.

[0446] A solution of triphenylphosphine (168 mg, 0.64 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (114 mg, 0.64 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for5 min and then allowed to warm to 25° C. where it was stirred for 25min. The reaction mixture was then treated with 2-aminothiazole (117 mg,1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15h. The crude reaction mixture was then directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) to afford2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(214 mg, 88%) as a yellow solid: mp 106-107° C.; EI-HRMS m/e calcd forC₁₈H₂₁BrN₂O₃S₂ (M⁺) 456.0177, found 456.0175.

EXAMPLE 732-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0447]

[0448] A solution of triphenylphosphine (168 mg, 0.64 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (114 mg, 0.64 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 72, 200 mg, 0.53 mmol). The resulting reactionmixture was stirred at 0° C. for 5 min and then allowed to warm to 25°C. where it was stirred for 25 min. The reaction mixture was thentreated with 2-aminopyridine (110 mg, 1.17 mmol). The resulting reactionmixture was stirred at 25° C. for 15 h. The crude reaction mixture wasthen directly purified by flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) to afford2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide(175 mg, 73%) as a white foam: mp 99-101° C.; FAB-HRMS m/e calcd forC₂₀H₂₃BrN₂O₃S (M+H)⁺451.0692, found 451.0689.

EXAMPLE 742-(3-Bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-propionamide

[0449]

[0450] A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (104 mg, 0.59 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 72, 200 mg, 0.53 mmol). The resulting reactionmixture was stirred at 0° C. for 5 min and then allowed to warm to 25°C. where it was stirred for 30 min. The reaction mixture was thentreated with 2-amino-5-bromopyridine (203 mg, 1.17 mmol). The resultingreaction mixture was stirred at 25° C. for 15 h. The crude reactionmixture was then directly purified by flash chromatography (Merck Silicagel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford the2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-propionamide(164 mg, 58%) as a white foam: mp 83-86° C. (foam to gel); FAB-HRMS m/ecalcd for C₂₀H₂₂Br₂N₂O₃S (M+H)⁺528.9796, found 528.9783.

EXAMPLE 752-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0451]

[0452] A mixture of2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (prepared as in Example 72, 990.0 mg, 2.54 mmol) and copper(I)cyanide (273.3 mg, 3.05 mmol) in dry N,N-dimethylformamide (2.5 mL) washeated under reflux for 4 h. The reaction was allowed to cool to 25° C.,and the crude reaction mixture was directly purified without furtherchemical work-up. Flash chromatography (Merck Silica gel 60, 70-230mesh, 100% hexanes then 3/1 hexanes/ethyl acetate) afforded2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (646.5 mg, 76%) as a very light yellow oil: EI-HRMS m/e calcd forC₁₇H₂₁NO₄S (M⁺) 335.1191, found 335.1185.

[0453] A solution of2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (4.84 g, 14.4 mol) in tetrahydrofuran (25 mL) was treated with a0.8M aqueous lithium hydroxide solution (27 mL, 21.6 mmol). The reactionmixture was stirred at 25° C. for 2.5 h. The reaction mixture waspartitioned between water and ethyl acetate and then acidified to pH=2with a 10% aqueous hydrochloric acid solution. The layers were shakenand separated. The resulting organic layer was washed with a saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated in vacuo to afford crude2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (3.80g, 82%) as a pale yellow oil that solidified to a pale yellow solid. Ananalytical sample was obtained by recrystallization from ethyl acetateto afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionicacid as a white solid: mp 180-181° C.; EI-HRMS m/e calcd for C₁₆H₁₉NO₄S(M⁺) 321.1034, found 321.1039.

[0454] A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylenechloride (1 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirredat 0° C. for 15 min and then treated with2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100mg, 0.31 mmol). The resulting reaction mixture was stirred at 0° C. for5 min and then allowed to warm to 25° C. where it was stirred for 30min. The reaction mixture was then treated with 2-aminothiazole (68 mg,0.68 mmol). The resulting reaction mixture was stirred at 25° C. for 15h. The crude reaction mixture was then directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) to afford2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(117 mg, 93%) as a white solid: mp 145-148° C.; EI-HRMS m/e calcd forC₁₉H₂₁N₃O₃S₂ (M⁺) 403.1024, found 403.1023.

EXAMPLE 762-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0455]

[0456] A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylenechloride (1 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirredat 0° C. for 15 min and then treated with2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 75, 100 mg, 0.31 mmol). The resulting reactionmixture was stirred at 0° C. for 5 min and then allowed to warm to 25°C. where it was stirred for 30 min. The reaction mixture was thentreated with 2-aminopyridine (64 mg, 0.68 mmol). The resulting reactionmixture was stirred at 25° C. for 15 h. The crude reaction mixture wasthen directly purified by flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) to afford2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide(94.5 mg, 76%) as a yellow foam: mp 87-90° C. (foam to gel); EI-HRMS m/ecalcd for C₂₁H₂₃N₃O₃S (M⁺) 397.1460, found 397.1460.

EXAMPLE 773-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0457]

[0458] A mixture of aluminum chloride (72.35 g, 0.54 mol) in chloroform(181 mL) was cooled to 0° C. and stirred until the solid materialdissolved. The reaction mixture was then slowly treated with ethyloxalyl chloride (61 mL, 0.54 mol), and the resulting reaction mixturewas stirred at 0° C. for 30 min. The reaction mixture was then slowlytreated with ethyl phenyl sulfide (25.00 g, 0.18 mol). The solutionturned to a wine color and slowly became gum-like. The resultingreaction mixture was then stirred at 0° C. for 2 h. The reaction mixturewas slowly poured into a large amount of ice/water. The resultingaqueous layer was extracted with chloroform (3×200 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 9/1 hexanes/ethyl acetate) afforded(4-ethylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (23.64 g, 55%) as ayellow oil. The material was used without further purification andcharacterization in subsequent reactions.

[0459] A solution of iodomethylcyclopentane (4.60 g, 21.89 mmol) andtriphenylphosphine (5.74 g, 21.89 mmol) in acetonitrile (22 mL) washeated under reflux for 2 weeks. The reaction mixture was allowed tocool to 25° C. and then concentrated in vacuo to provide an orangesolid. The orange solid was triturated with diethyl ether and thenfiltered. The solid was washed well with diethyl ether until thewashings showed the absence of iodomethylcyclopentane andtriphenylphosphine by thin layer chromatography. The solid was allowedto air dry to afford cyclopentylmethyl triphenylphosphonium iodide (8.92g, 86%) as a light orange solid: mp 195-198° C.; FAB-HRMS m/e calcd forC₂₄H₂₆P (M+H)⁺345.1772, found 345.1784.

[0460] A suspension of cyclopentylmethyl triphenylphosphonium iodide(24.48 g, 51.82 mmol) in dry tetrahydrofuran (100 mL) was cooled to 0°C. and then treated dropwise with a 1.0M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (52 mL, 51.82 mmol). Thebright orange reaction mixture was stirred at 0° C. for 1 h. Thereaction mixture was then treated with(4-ethylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (9.50 g, 39.87mmol). The resulting reaction mixture was allowed to warm to 25° C.where it was stirred for 20 h. The reaction mixture was concentrated invacuo to remove tetrahydrofuran and then diluted with water (300 mL).The aqueous layer was extracted with ethyl acetate (3×200 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×200 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 19/1 hexanes/ethyl acetate) afforded the3-cyclopentyl-2-(4-ethylsulfanyl-phenyl)-acrylic acid ethyl ester (6.08g, 50%) as a yellow oil containing a 1.82:1 mixture of (E):(Z) isomers:FAB-LRMS m/e calcd for C₁₈H₂₄O₂S (M+H)⁺integer mass 304, found 305. Theisomeric mixture was used without further separation in subsequentreactions.

[0461] A solution of 3-cyclopentyl-2-(4-ethylsulfanyl-phenyl)-acrylicacid ethyl ester [5.76 g, 18.92 mmol, (E):(Z)=1.82:1] in methylenechloride (47 mL) was slowly treated with 3-chloroperoxybenzoic acid(57-86% grade, 11.45 g based on 57%, 37.83 mmol). The reaction mixturewas stirred at 25° C. for 1 h. The reaction mixture was concentrated invacuo to remove methylene chloride. The resulting residue was dilutedwith diethyl ether (300 mL). The organic phase was washed with asaturated aqueous sodium bicarbonate solution (3×200 mL) and a saturatedaqueous sodium chloride solution (1×200 mL), dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylic acid ethyl ester (4.89g, 77%) as a colorless oil. The product was a 3:1 mixture of (E):(Z)isomers that was used without further purification and characterization.

[0462] A solution of 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylicacid ethyl ester [4.89 g, 14.53 mmol, (E):(Z)=3:1] in ethanol (36 mL)was slowly treated with 10% palladium on activated carbon (244.5 mg).The reaction mixture was stirred under a positive pressure of hydrogengas (balloon) at 25° C. and atmospheric pressure for 44 h. The catalystwas then filtered off through a pad of celite, and the celite pad waswashed well with ethyl acetate. The filtrate was concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester(3.50 g, 71%) as a colorless viscous oil: FAB-LRMS m/e calcd forC₁₈H₂₆O₄S (M+H)⁺integer mass 338, found 339.

[0463] A solution of 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionicacid ethyl ester (2.50 g, 7.39 mmol) in tetrahydrofuran (30 mL) wastreated with a 0.8M aqueous lithium hydroxide solution (11.1 mL, 8.86mmol). The reaction mixture was stirred at 25° C. for 23 h. Theresulting reaction mixture was partitioned between water (75 mL) andethyl acetate (75 mL) and then treated with a 1N aqueous hydrochloricacid solution (15 mL). The layers were shaken and separated. The organiclayer was dried over magnesium sulfate, filtered, and concentrated invacuo to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid(2.20 g, 96%) as a white solid which was used without furtherpurification: mp 137-138° C.; FAB-HRMS m/e calcd for C₁₆H₂₂O₄S(M+H)⁺311.1317, found 311.1321.

[0464] A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylenechloride (5 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (189 mg, 1.06 mmol). The reaction mixture was stirredat 0° C. for 20 min and then treated with3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (300 mg, 0.97mmol). The resulting reaction mixture was stirred at 0° C. for 10 minand then allowed to warm to 25° C. where it was stirred for 30 min. Thereaction mixture was then treated with 2-aminothiazole (213 mg, 2.13mmol). The resulting reaction mixture was stirred at 25° C. for 15 h.The crude reaction mixture was then directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) to afford3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(330 mg, 87%) as a pale yellow solid: mp 178-179° C.; EI-HRMS m/e calcdfor C₁₉H₂₄N₂O₃S₂ (M⁺) 392.1228, found 392.1230.

EXAMPLE 783-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide

[0465]

[0466] A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylenechloride (5 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (189 mg, 1.06 mmol). The reaction mixture was stirredat 0° C. for 20 min and then treated with3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (prepared as inExample 77, 300 mg, 0.97 mmol). The resulting reaction mixture wasstirred at 0° C. for 10 min and then allowed to warm to 25° C. where itwas stirred for 30 min. The reaction mixture was then treated with2-aminopyridine (200 mg, 2.13 mmol). The resulting reaction mixture wasstirred at 25° C. for 15 h. The crude reaction mixture was then directlypurified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1hexanes/ethyl acetate) to afford3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide(185 mg, 50%) as a pale orange solid: mp 144-145° C.; EI-HRMS m/e calcdfor C₂₁H₂₆N₂O₃S (M⁺) 386.1664, found 386.1660.

EXAMPLE 792-(3,4-Bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0467]

[0468] A solution of 3,4-difluorophenylacetic acid (5.00 g, 29.05 mmol)in methanol (73 mL) was slowly treated with concentrated sulfuric acid(4 mL). The resulting reaction mixture was heated under reflux for 65 h.The reaction mixture was allowed to cool to 25° C. and then concentratedin vacuo to remove methanol. The resulting residue was slowly dilutedwith a saturated aqueous sodium bicarbonate solution (300 mL) and thenextracted with ethyl acetate (1×300 mL). The organic layer was driedover magnesium sulfate, filtered, and concentrated in vacuo to afford(3,4-difluoro-phenyl)-acetic acid methyl ester (5.38 g, 99%) as a yellowoil which was used without further purification.

[0469] A solution of sodium thiomethoxide (6.39 g, 86.69 mmol) indimethyl sulfoxide (72 mL) was treated with (3,4-difluoro-phenyl)-aceticacid methyl ester (5.38 g, 28.89 mmol). The reaction mixture was stirredat 25° C. for 2 h then heated at 70° C. for 15 min, at which time, thinlayer chromatography indicated the absence of starting material and thepresence of a very polar new product. The reaction indicated that theester hydrolyzed to the acid upon heating. The resulting reactionmixture was allowed to cool to 25° C. The reaction mixture was thentreated with a 10% aqueous hydrochloric acid solution (200 mL) and thenextracted with chloroform (3×200 mL). The combined organic layers weredried over magnesium sulfate, filtered, and concentrated in vacuo toafford a yellow oil. This yellow oil was dissolved in methanol (100 mL)and then slowly treated with concentrated sulfuric acid (5 mL). Theresulting reaction mixture was heated under reflux for 3 h. The reactionmixture was allowed to cool to 25° C. and then concentrated in vacuo toremove methanol. The resulting residue was slowly diluted with asaturated aqueous sodium bicarbonate solution (300 mL) and thenextracted with ethyl acetate (1×300 mL). The organic layer was driedover magnesium sulfate, filtered, and concentrated in vacuo to afford aninseparable, isomeric mixture of(3-fluoro-4-methylsulfanyl-phenyl)-acetic acid methyl ester and(4-fluoro-3-methylsulfanyl-phenyl)-acetic acid methyl ester as a yellowoil (4.65 g, 75%) which was used without further purification andcharacterization.

[0470] A solution of the inseparable, isomeric mixture of(3-fluoro-4-methylsulfanyl-phenyl)-acetic acid methyl ester and(4-fluoro-3-methylsulfanyl-phenyl)-acetic acid methyl ester (4.44 g,20.72 mmol) in methylene chloride (103 mL) was slowly treated with3-chloroperoxybenzoic acid (57-86% grade, 13.80 g based on 57%, 45.59mmol). The reaction mixture was stirred at 25° C. for 4 h. The reactionmixture was concentrated in vacuo to remove methylene chloride. Theresulting residue was diluted with ethyl acetate (300 mL). The organicphase was washed with a saturated aqueous sodium bicarbonate solution(1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL),dried over magnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 70-230 mesh, 20/1 methylenechloride/ethyl acetate) afforded an inseparable, isomeric mixture of(3-fluoro-4-methanesulfonyl-phenyl)-acetic acid methyl ester and(4-fluoro-3-methanesulfonyl-phenyl)-acetic acid methyl ester as acolorless liquid (3.31 g, 65%) which was used without furtherpurification and characterization.

[0471] A solution of the inseparable, isomeric mixture of(3-fluoro-4-methanesulfonyl-phenyl)-acetic acid methyl ester and(4-fluoro-3-methanesulfonyl-phenyl)-acetic acid methyl ester (2.28 g,9.26 mmol) in dimethyl sulfoxide (23 mL) was treated with sodiumthiomethoxide (1.37 g, 18.52 mmol). The reaction mixture was stirred at25° C. for 4 h and then quenched with a 10% aqueous hydrochloric acidsolution. The aqueous layer was extracted with chloroform (1×400 mL),dried over magnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethylacetate) afforded an inseparable, isomeric mixture of(3-methanesulfonyl-4-methylsulfanyl-phenyl)-acetic acid methyl ester and(4-methanesulfonyl-3-methylsulfanyl-phenyl)-acetic acid methyl ester asa yellow liquid (2.19 g, 86%) which was used without furtherpurification and characterization.

[0472] A solution of the inseparable, isomeric mixture of(3-methanesulfonyl-4-methylsulfanyl-phenyl)-acetic acid methyl ester and(4-methanesulfonyl-3-methylsulfanyl-phenyl)-acetic acid methyl ester(2.19 g, 7.98 mmol) in methylene chloride (20 mL) was slowly treatedwith 3-chloroperoxybenzoic acid (57-86% grade, 6.41 g based on 57%,31.93 mmol). The reaction mixture was stirred at 25° C. for 5 h and thenslowly quenched with a 1.5N aqueous sodium sulfite solution. Theresulting reaction mixture was extracted with methylene chloride (300mL). The organic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 10/1 methylene chloride/ethyl acetate) afforded(3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester (1.89 g, 77%)as a white solid: mp 157-158° C.; EI-HRMS m/e calcd for C₁₁H₁₄O₆S₂ (M⁺)306.0232, found 306.0234.

[0473] A solution of diisopropylamine (951 μL, 6.79 mmol) in drytetrahydrofuran (6 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL) was cooled to−78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (2.5 mL, 6.79 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of (3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester(1.89 g, 6.17 mmol) in dry tetrahydrofuran (12 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The resultingreaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (1.56 g, 7.40 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas allowed to warm to 25° C. where it was stirred for 64 h. Thereaction mixture was quenched with water (150 mL) and then concentratedin vacuo to remove tetrahydrofuran. The remaining residue was furtherdiluted with water (100 mL) and then extracted with ethyl acetate (1×250mL). The organic layer was washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over magnesium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,70-230 mesh, 3/1 hexanes/ethyl acetate) afforded2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (1.61 g, 67%) as a yellow oil: EI-HRMS m/e calcd for C₁₇H₂₄O₆S₂(M⁺) 388.1014, found 388.1014.

[0474] A solution of2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (1.17 g, 3.01 mmol) in tetrahydrofuran (12 mL) was treated with a0.8M aqueous lithium hydroxide solution (5.6 mL, 4.52 mmol). Thereaction mixture was stirred at 25° C. for 3 h. The resulting reactionmixture was partitioned between water (75 mL) and ethyl acetate (75 mL)and then treated with a 1N aqueous hydrochloric acid solution (10 mL).The layers were shaken and separated. The organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.10 g,98%) as a white foam which was used without further purification: mp64-68° C. (foam to gel); FAB-HRMS m/e calcd for C₁₆H₂₂O₆S₂(M+H)⁺375.0936, found 375.0932.

[0475] A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylenechloride (2 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (105 mg, 0.59 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg,0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5min and then allowed to warm to 25° C. where it was stirred for 30 min.The reaction mixture was then treated with 2-aminothiazole (118 mg, 1.18mmol). The resulting reaction mixture was stirred at 25° C. for 15 h.The crude reaction mixture was then directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) to afford2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(150 mg, 61%) as a pale yellow foam: mp 104-107° C.; EI-HRMS m/e calcdfor C₁₉H₂₄N₂O₅S₃ (M⁺) 456.0847, found 456.0846.

EXAMPLE 802-(3,4-Bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0476]

[0477] A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylenechloride (2 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (105 mg, 0.59 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 79, 200 mg, 0.53 mmol). The resulting reactionmixture was stirred at 0° C. for 5 min and then allowed to warm to 25°C. where it was stirred for 30 min. The reaction mixture was thentreated with 2-aminopyridine (110 mg, 1.18 mmol). The resulting reactionmixture was stirred at 25° C. for 15 h. The crude reaction mixture wasthen directly purified by flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) to afford2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide(117 mg, 49%) as a pale yellow foam: mp 107-110° C.; EI-HRMS m/e calcdfor C₂₁H₂₆N₂O₅S₂ (M⁺) 450.1283, found 450.1282.

EXAMPLE 813-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]triazin-3-yl-propionamide

[0478]

[0479] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(prepared as in Example 38A, 400 mg, 1.40 mmol) in dry pyridine (5 mL)was treated with 1,3-dicyclohexylcarbodiimide (316 mg, 1.53 mmol). Thereaction mixture was stirred at 25° C. for 3.5 h and then treated with3-amino-1,2,4-triazine (296 mg, 3.08 mmol) and an additional amount ofpyridine (1 mL). The reaction mixture was warmed at 100° C. for 20 h.The reaction mixture was concentrated in vacuo to remove pyridine. Theresulting residue was diluted with ethyl acetate then filtered. Thefiltrate was washed with a 1N aqueous hydrochloric acid solution andwashed with water. The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 1/1 ethyl acetate/hexanes) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]triazin-3-yl-propionamide(40.9 mg, 8%) as a yellow-orange solid: mp 81-83° C.; EI-HRMS m/e calcdfor C₁₇H₁₈Cl₂N₄O (M⁺) 364.0858, found 364.0857.

EXAMPLE 823-Cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide

[0480]

[0481] A solution of diisopropylamine (559 μL, 3.99 mmol) in drytetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and thentreated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99mmol). The resulting reaction mixture was allowed to warm to 0° C. andthen was treated with3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(prepared as in Example 3A, 463.1 mg, 1.22 mmol) in small portions. Thereaction mixture turned orange in color. The reaction mixture was thenallowed to warm to 25° C. where it was stirred for 30 min. After 30 minat 25° C., the reaction mixture was cooled back down to 0° C. and thentreated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL,1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10min then allowed to warm to 25° C. The reaction mixture was stirred at25° C. for 30 min then heated under reflux for 20 h. The reactionmixture was cooled to 0° C. and then treated with water (3 mL) followedby sodium acetate (702.5 mg, 8.56 mmol) and then finallyhydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resultingreaction mixture was stirred at 0° C. for 30 min then allowed to warm to25° C. where it was stirred for 44 h. The reaction mixture wasconcentrated in vacuo to remove tetrahydrofuran. The resulting aqueousresidue was diluted with ethyl acetate (150 mL). The organic layer waswashed with a saturated aqueous sodium bicarbonate solution (1×100 mL)and a saturated aqueous sodium chloride solution (1×100 mL), dried oversodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethylacetate) afforded3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8mg, 72%) as a white solid: mp 179-181° C.; EI-HRMS m/e calcd forC₁₇H₂₁N₃O₂S₂ (M⁺) 379.1024, found 379.1029.

EXAMPLE 833-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide

[0482]

[0483] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid(prepared as in Example 38A, 200.0 mg, 0.70 mmol),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(316.9 mg, 0.84 mmol), N,N-diisopropylethylamine (365 mL, 2.09 mmol),and 2-amino-1,3,4-thiadiazole (140.8 mg, 1.39 mmol) in dryN,N-dimethylformamide (2 mL) was stirred at 25° C. under nitrogen for 20h. The reaction mixture was concentrated in vacuo to removeN,N-dimethylformamide. The resulting residue was diluted with ethylacetate (100 mL). The organic layer was washed sequentially with asaturated aqueous sodium bicarbonate solution (1×50 mL), a 10% aqueoushydrochloric acid solution (1×100 mL), and a saturated aqueous sodiumchloride solution (1×100 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide(197.3 mg, 77%) as a white foam: mp 90-91° C.; EI-HRMS m/e calcd forC₁₆H₁₇Cl₂N₃OS (M⁺) 369.0469, found 369.0476.

EXAMPLE 84 2-(4-Cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0484]

[0485] A solution of freshly prepared lithium diisopropylamide (23 mL ofa 0.32M stock solution, 7.13 mmol) cooled to −78° C. was treated with(4-bromo-phenyl)-acetic acid methyl ester (1.48 g, 6.48 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.2mL, 3:1). The resulting solution was stirred at −78° C. for 45 min.Iodomethylcyclopentane (1.49 g, 7.13 mmol) was then added in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reactionmixture was stirred at −78° C. for 4 h. The reaction was then warmed to25° C. and was stirred at 25° C. for 18 h. The reaction mixture was thenquenched by the dropwise addition of a saturated aqueous ammoniumchloride solution (10 mL). This mixture was poured into water (100 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with a saturated aqueous lithium chloride solution (1×50mL), dried over sodium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5hexanes/ethyl acetate) afforded2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.60 g,79.3%) as a clear oil: EI-HRMS m/e calcd for C₁₅H₁₉O₂Br (M⁺) 310.0568found 310.0564.

[0486] A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acidmethyl ester (500 mg, 1.60 mmol) in N,N-dimethylformamide (4.01 mL) wastreated with copper(I) cyanide (144 mg, 1.60 mmol). The mixture washeated at 170° C. for 1 h. At this time, the reaction was cooled to 25°C. and poured into aqueous ammonium hydroxide (5 mL). The solution wasdiluted with water (25 mL) and extracted with ethyl acetate (3×35 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 90/10 hexanes/ethyl acetate) afforded2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.6 g,15.8%) as a clear oil: EI-HRMS m/e calcd for C₁₆H₁₉NO₂ (M⁺) 257.1415found 257.1406.

[0487] A solution of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acidmethyl ester (65.0 mg, 0.25 mmol) in tetrahydrofuran/water/methanol (2.5mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution(0.27 mL, 0.27 mmol). The reaction was stirred at 25° C. for 6 h. Atthis time, the reaction was acidified to pH=1 with a 1N aqueoushydrochloric acid solution and extracted with chloroform/methanol (9:1,3×25 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid (36.0 mg, 58.6%) as awhite solid: mp 126-128° C.; EI-HRMS m/e calcd for C₁₅H₁₇NO₂ (M⁺)243.1259 found 243.1268.

[0488] A solution of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid(33.0 mg, 0.13 mmol) in methylene chloride (1.36 mL) was cooled to 0° C.and then treated with a 2.0M solution of oxalyl chloride in methylenechloride (0.07 mL, 0.14 mmol) and a few drops of N,N-dimethylformamide.The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for30 min. The reaction mixture was then treated with a solution of2-aminothiazole (30.0 mg, 0.29 mmol) and N,N-diisopropylethylamine (0.05mL, 0.32 mmol) in tetrahydrofuran (0.67 mL). This solution was stirredat 25° C. for 3 h. At this time, the reaction was concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50hexanes/ethyl acetate) afforded2-(4-cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (44.1 mg,100%) as a white solid: mp 64-66° C.; EI-HRMS m/e calcd for C₁₈H₁₉N₃OS(M⁺) 325.1248 found 325.1247.

[0489] In an analogous manner, there was obtained:

[0490] a) From 2-aminopyridine and2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid:2-(4-Cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide as a whitesolid: mp 61-63° C.; EI-HRMS m/e calcd for C₂₀H₂₁N₃O (M⁺) 319.1684,found 319.1697.

[0491] b) From 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid and6-amino-nicotinic acid methyl ester:6-[2-(4-Cyano-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester as a white solid: mp 62-64° C.; EI-HRMS m/e calcd forC₂₂H₂₃N₃O₃(M⁺) 377.1739, found 377.1736.

EXAMPLE 853-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide

[0492]

[0493] A solution of freshly prepared lithium diisopropylamide (23 mL ofa 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with(4-trifluoromethyl)phenylacetic acid (693 mg, 3.4 mmol) intetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resultingsolution was stirred at −78° C. for 30 min. Iodomethylcyclopentane (784mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). Thereaction mixture was stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 16 h. The reactionmixture was then quenched by the dropwise addition of saturated aqueousammonium chloride solution (10 mL). The excess solvent was removed invacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloricacid solution. The mixture was poured into water (150 mL) and extractedwith ethyl acetate (3×100 mL). The organics were dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9 mg,65%) as a white solid: mp 94-95° C.; FAB-HRMS m/e calcd forC₁₅H₁₇F₃O₂(M+Na)⁺309.1079, found 309.1072.

[0494] A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (170 mg, 0.38 mmol),3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (100 mg, 0.34mmol), and 2-aminopyridine (36 mg, 0.38 mmol) in N,N-dimethylformamide(1.75 mL) was treated with N,N-diisopropylethylamine (0.12 mL, 0.73mmol). The reaction mixture was stirred at 25° C. for 18 h. At thistime, the reaction was poured into water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed with a1N aqueous hydrochloric acid solution (1×50 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate)afforded3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide(127 mg, 53.3%) as a white gum: EI-HRMS m/e calcd for C₂₀H₂₁F₃N₂O (M⁺)362.1605, found 362.1592.

[0495] In an analogous manner, there was obtained:

[0496] a) From 6-amino-nicotinic acid methyl ester and3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic:6-[3-Cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionylamino]-nicotinicacid methyl ester as a white gum: EI-HRMS m/e calcd for C₂₂H₂₃F₃N₂O₃(M⁺) 420.1660, found 420.1661.

EXAMPLE 862-[4-(Butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0497]

[0498] A solution of freshly prepared lithium diisopropylamide (430.55mL of a 0.3M stock solution, 129.16 mmol) cooled to −78° C. was treatedwith (4-nitro-phenyl)-acetic acid ethyl ester (prepared as in Example22A, 26.32 g, 125.83 mmol) in tetrahydrofuran/hexamethylphosphoramide(312.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45min. Iodomethylcyclopentane (27.75 g, 132.1 mmol) was then added inhexamethylphosphoramide (27.75 mL). The mixture was stirred at −78° C.for 4 h. The reaction was then warmed to 25° C. and was stirred at 25°C. for 16 h. The reaction mixture was then quenched by the dropwiseaddition of a saturated aqueous ammonium chloride solution (250 mL).This mixture was concentrated in vacuo. The residue was diluted withwater (250 mL) and extracted with ethyl acetate (3×300 mL). The combinedorganic layers were washed with a saturated aqueous lithium chloridesolution (2×250 mL), dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 98/2 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (28.30 g,77.2%) as a yellow oil: EI-HRMS m/e calcd for C₁₆H₂₁NO₄ (M⁺) 291.1470,found 291.1470.

[0499] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acidethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was treatedwith 10% palladium on activated carbon. The reaction mixture was stirredunder hydrogen gas at 60 psi at 25° C. for 18 h. The catalyst was thenfiltered off through a pad of celite, which was washed well with ethylacetate. The resulting filtrate was concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethylacetate) afforded 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethylester (3.52 mg, 53.3%) as a yellow oil: EI-HRMS m/e calcd for C₁₆H₂₃NO₂(M⁺) 261.1729 found 261.1727.

[0500] A mixture of concentrated hydrochloric acid (0.38 mL) and ice(380 mg) cooled to 0° C. was treated with2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (497 mg,1.90 mmol). After 5 min, a solution of sodium nitrite (139 mg, 2.01mmol) in water (0.31 mL) was added to the reaction mixture. Theresulting solution was stirred at 0° C. for 5 min. At this time, thesolution was added to a solution of n-butyl mercaptan (0.23 mL, 2.20mmol) in water (0.41 mL) warmed to 45° C. The reaction was stirred at45° C. for 3 h. At this time, the reaction was diluted with water (50mL) and extracted with chloroform (3×50 mL). The organics were driedover sodium sulfate, filtered, and concentrated in vacuo. The crudebrown oil (588 mg) in methylene chloride (8.8 mL) was cooled to 0° C.and treated with 3-chloroperoxybenzoic acid (80-85% grade, 1.5 g, 8.78mmol). The reaction mixture was stirred at 25° C. for 18 h. At thistime, the reaction was diluted with water (75 mL) and extracted withchloroform (2×30 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)afforded 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acidethyl ester (144.3 mg, 20.7%) as a yellow oil: EI-HRMS m/e calcd forC₂₀H₃₀O₄S (M⁺) 366.1865 found 366.1858.

[0501] A solution of2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid ethylester (140 mg, 0.38 mmol in tetrahydrofuran/water/methanol (0.95 mL,3:1:1) was treated with a 1N aqueous lithium hydroxide solution (0.76mL, 0.76 mmol). The reaction was stirred at 25° C. for 8 h. At thistime, the reaction was acidified to pH=l with a 1N aqueous hydrochloricacid solution and extracted with chloroform (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 90/10 chloroform/methanol) afforded2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (88.3 mg,68.4%) as a clear oil: FAB-HRMS m/e calcd for C₁₈H₂₆O₄S (M+H)⁺339.1631found 339.1638.

[0502] A solution of triphenylphosphine (99 mg, 0.37 mmol) andN-bromosuccinimide (76 mg, 0.42 mmol) in methylene chloride (1.26 mL)cooled to 0° C. was treated with2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (85 mg,0.25 mmol) in methylene chloride. The reaction mixture was stirred at25° C. for 45 min. At this time, the reaction was treated with2-aminothiazole (33 mg, 0.32 mmol) and pyridine (0.03 mL, 0.37 mmol).The reaction was stirred at 25° C. for 18 h. The reaction mixture wasthen concentrated in vacuo to remove methylene chloride. At this time,the reaction was diluted with water (50 mL) and extracted withchloroform (3×50 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 70-230 mesh, 50/50 hexanes/ethyl acetate) afforded2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide(69.3 mg, 65.6%) as an off-white solid: mp 163-165° C.; EI-HRMS m/ecalcd for C₂₁H₂₈N₂O₃S₂ (M⁺) 420.1541 found 420.1535.

[0503] In an analogous manner, there was obtained:

[0504] a) From 2-aminothiazole and3-cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-propionic acid:3-Cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-N-thiazol-2-yl-propionamideas a yellow oil: EI-HRMS m/e calcd for C₂₀H₂₆N₂O₃S₂ (M⁺) 406.1385 found406.1389.

EXAMPLE 873-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide

[0505]

[0506] A solution of freshly prepared lithium diisopropylamide (35.32 mLof a 0.31M stock solution, 10.95 mmol) cooled to −78° C. was treatedwith (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (1.11 g, 5.0 mmol)in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone(12.42 mL, 3:1). The resulting solution was then stirred at −78° C. for1 h. Iodomethylcyclopentane (1.16 g, 5.52 mmol) was then added in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 mL). Thereaction mixture was stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 24 h. This solution wasthen quenched by the slow addition of the reaction mixture to a 2Naqueous hydrochloric acid solution (50 mL). The product was extractedinto ethyl acetate (1×300 mL) and diethyl ether (1×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (1.28g, 84.3%) as a white solid: mp 65-68° C.; EI-HRMS m/e calcd forC₁₅H₁₆F₄O₂(M⁺) 305.1165, found 305.1174.

[0507] A solution of3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (304mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. and thentreated with a 2.0M solution of oxalyl chloride in methylene chloride(0.6 mL, 1.2 mmol) and a few drops of N,N-dimethylformamide. Thereaction mixture was stirred at 0° C. for 15 min and at 25° C. for 24 h.The reaction mixture was then treated with 2-amino-thiazole (175 mg,1.75 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.41 mmol). Thissolution was stirred at 25° C. for 48 h. At this time, the reaction wasconcentrated in vacuo. High pressure liquid chromatography(Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 60/40 heptane/ethylacetate) afforded3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide(326 mg, 84.5%) as a light yellow solid: mp 125-127° C.; EI-HRMS m/ecalcd for C₁₈H₁₈F₄N₂OS (M⁺) 386.1076, found 386.1086.

[0508] In an analogous manner, there was obtained:

[0509] a) From ethyl 2-amino-4-thiazole glyoxylate and3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid:{2-[3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester as a light yellow solid: mp 155-158° C.; FAB-HRMS m/ecalcd for C₂₂H₂₂F₄N₂O₄S (M+H)⁺487.1314, found 487.1319.

[0510] b) From 5-methyl-2-aminopyridine and3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid:3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamideas a white solid: mp 132-133° C.; EI-HRMS m/e calcd for C₂₁H₂₂F₄N₂O (M⁺)392.1668, found 392.1669.

[0511] c) From 2-aminopyridine and3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid:3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamideas a light yellow oil: EI-HRMS m/e calcd for C₂₀H₂₀F₄N₂O (M⁺) 380.1511,found 380.1521.

EXAMPLE 883-Cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide

[0512]

[0513] A solution of freshly prepared lithium diisopropylamide (35.32 mLof a 0.31M stock solution, 10.9 mmol) cooled to −78° C. was treated with(3-trifluoromethyl-phenyl)-acetic acid (1.02 g, 5.0 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.4mL, 3:1). The resulting solution was stirred at −78° C. for 3 h.Iodomethylcyclopentane (1.16 g, 5.52 mmol) was then added in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). Thereaction mixture was stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 48 h. This solution wasthen quenched by the slow addition of the reaction mixture to a 2Naqueous hydrochloric acid solution (50 mL). The product was extractedinto ethyl acetate (3×100 mL) and diethyl ether (1×50 mL). The combinedorganic layers were washed with a saturated aqueous lithium chloridesolution (2×100 mL) and a saturated aqueous sodium chloride solution(1×150 mL), dried over magnesium sulfate and sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (1.16 g,80.5%) as an off-white solid: mp 64-65° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₂ (M+Na⁺) 309.1079, found 309.1084.

[0514] A solution of3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (286 mg, 1.0mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treatedwith a 2.0M solution of oxalyl chloride in methylene chloride (0.6 mL,1.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixturewas stirred at 0° C. for 15 min and at 25° C. for 1.25 h. The reactionmixture was then treated with a solution of 2-aminothiazole (175 mg,1.75 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.41 mmol) intetrahydrofuran (10 mL). This solution was stirred at 25° C. for 24 h.At this time, the reaction was concentrated in vacuo. High pressureliquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cmID, 60/40 heptane/ethyl acetate) afforded3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide(299.2 mg, 81.4%) as a light yellow solid: mp 134-136° C.; EI-HRMS m/ecalcd for C₁₈H₁₉F₃N₂OS (M⁺) 368.1170, found 368.1165.

EXAMPLE 893-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide

[0515]

[0516] A solution of3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid(prepared as in Example 87 Å, 7.77 g, 25.3 mmol) in methanol (50 mL) wastreated slowly with concentrated sulfuric acid (0.01 mL). The resultingreaction mixture was heated under reflux for 24 h. The reaction mixturewas allowed to cool to 25° C. and then concentrated in vacuo. Theresidue was dissolved in ethyl acetate (75 mL). The organic layer waswashed with a saturated aqueous sodium bicarbonate solution (1×50 mL),water (1×50 mL), and a saturated aqueous sodium chloride solution (4×50mL). The organic layer was then dried over magnesium sulfate and sodiumsulfate, filtered, and concentrated in vacuo to afford3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acidmethyl ester (8.48 g, 87.5%) as yellow oil: EI-HRMS m/e calcd forC₁₆H₁₈F₄O₂ (M⁺) 318.1243, found 318.1240.

[0517] A solution of3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acidmethyl ester (7.0 g, 21.9 mmol) in N,N-dimethylformamide (50 mL) wastreated with sodium methanethiolate (2.61 g, 33.0 mmol). The reactionmixture was then heated at 100-110° C for 24 h. At this time, thereaction was poured onto a mixture of ice and a 2N aqueous hydrochloricacid solution (100 mL). This mixture was extracted into ethyl acetate(3×75 mL) and diethyl ether (1×50 mL). The combined organic layers werethen washed with water (1×75 mL) and a saturated aqueous sodium chloridesolution (3×100 mL). The organic layer was then dried over magnesiumsulfate and sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethylacetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (2.48 g, 35.5%) as a pale yellow oil: EI-HRMS m/ecalcd for C₁₇H₂₁F₃O₂S (M⁺) 346.1214, found 346.1212.

[0518] A solution of3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (2.36 g, 6.81 mmol) in methylene chloride (75 mL) at25° C. was treated with 3-chloroperoxybenzoic acid (80-85% grade, 9.69g, 40.1 mmol). The reaction mixture was stirred at 25° C. for 16 h. Atthis time, the reaction was diluted with methylene chloride (75 mL). Thesolution was washed sequentially with a saturated aqueous sodiumbisulfite solution (2×50 mL), water (1×50 mL), a saturated aqueoussodium chloride solution (3×75 mL), a saturated aqueous sodiumbicarbonate solution (1×75 mL), and a saturated aqueous sodium chloridesolution (3×75 mL). The organic layer was then dried over magnesiumsulfate and sodium sulfate, filtered, and concentrated in vacuo toafford3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (2.88 g) as a clear oil: EI-HRMS m/e calcd forC₁₇H₂₁F₃O₄S (M⁺) 378.1112 found 378.1116.

[0519] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (395 mg, 1.04 mmol) and 2-aminothiazole (209 mg, 1.38mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.09mL, 1.38 mmol) was heated at 110° C. for 24 h. The reaction mixture wasthen concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded the3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide(256.7 mg, 55.1%) as a white solid: mp 95-100° C.; EI-HRMS m/e calcd forC₁₉H₂₁F₃N₂O₃S₂ (M⁺)446.0946, found 446.0944.

[0520] In an analogous manner, there was obtained:

[0521] a) From (2-amino-thiazol-4-yl)-acetic acid methyl ester and3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid:{2-[3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester as a white solid: mp 81-86° C.; FAB-HRMS m/e calcd forC₂₂H₂₅F₃N₂O₅S₂ (M+H)⁺518.1157, found 518.1161.

[0522] b) From 2-amino-thiazole-4-carboxylic acid methyl ester and3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid:2-[3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester as a white solid: mp 117-121° C.; FAB-HRMS m/e calcdfor C₂₁H₂₃F₃N₂O₅S₂ (M+H)⁺504.1000, found 504.1000.

EXAMPLE 903-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide

[0523]

[0524] A solution of freshly prepared lithium diisopropylamide (141.28mL of a 0.31M stock solution, 43.8 mmol) cooled to −78° C. was treatedwith (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (4.44 g, 20.0 mmol)in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone(49.68 mL, 3:1). The resulting solution was then stirred at −78° C. for1 h. At this time, the reaction was treated with a solution ofiodomethylcyclopentane (4.64 g, 22.09 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.6 mL). Thereaction mixture was stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 48 h. This solution wasthen quenched by the slow addition of the reaction mixture to a 2Naqueous hydrochloric acid solution. The product was extracted into ethylacetate (3×400 mL) and diethyl ether (1×200 mL). The combined organiclayers were dried over magnesium sulfate and sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (3.37g, 55.4%) as a white solid: mp 66-68° C.; EI-HRMS m/e calcd forC₁₅H₁₆F₄O₂ (M⁺) 305.1165, found 305.1174.

[0525] A solution of3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (1.52g, 5.0 mmol) in N,N-dimethylformamide (10 mL) was treated with sodiummethanethiolate (0.59 g, 7.5 mmol). The reaction mixture was then heatedto 100-110° C. for 14 h. At this time, the reaction was poured onto amixture of ice and a 2N aqueous hydrochloric acid solution (25 mL). Thismixture was extracted into ethyl acetate (3×35 mL) and diethyl ether(1×25 mL). The combined organic layers were then washed with water (1×50mL) and a saturated aqueous sodium chloride solution (3×75 mL). Theorganic layer was then dried over magnesium sulfate and sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate w/acetic acid)afforded3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (1.36 g, 83.4%) as a pale yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1057.

[0526] A solution of3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (1.29 g, 3.89 mmol) in ethanol (25 mL) was treated slowly withconcentrated sulfuric acid (0.01 mL). The resulting reaction mixture washeated under reflux for 48 h. The reaction mixture was allowed to coolto 25° C. and then concentrated in vacuo. The residue was dissolved inethyl acetate (35 mL). The organic layer was washed with a saturatedaqueous sodium bicarbonate solution (1×15 mL), water (1×15 mL), and asaturated aqueous sodium chloride solution (3×20 mL). The organic layerwas then dried over magnesium sulfate and sodium sulfate, filtered, andconcentrated in vacuo to afford3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid ethyl ester (1.39 g, 94.8%) as yellow oil: EI-HRMS m/e calcd forC₁₈H₂₃F₃O₂S (M⁺) 360.1370, found 360.1370.

[0527] A solution of3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid ethyl ester (1.32 g, 3.69 mmol) in methylene chloride (50 mL) at25° C. was treated with 3-chloroperoxybenzoic acid (80-85% grade, 4.8 g,19.8 mmol). The reaction mixture was stirred at 25° C. for 4 d. At thistime, the reaction was diluted with methylene chloride (25 mL). Thissolution was washed sequentially with a saturated aqueous sodiumbisulfite solution (1×50 mL), water (1×50 mL), a saturated aqueoussodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturatedaqueous sodium chloride solution (3×50 mL). The organic layer was driedover magnesium sulfate and sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30hexanes/ethyl acetate with acetic acid) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid ethyl ester (1.28 g, 89.0%) as a clear oil: EI-HRMS m/e calcd forC₁₈H₂₃F₃O₄S (M⁺) 392.1269 found 392.1268.

[0528] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid ethyl ester (707 mg, 1.80 mmol in tetrahydrofuran/water (24 mL,3:1) was treated with lithium hydroxide (166 mg, 3.97 mmol). Thereaction was stirred at 25° C. for 24 h. At this time, the reactionconcentrated in vacuo. The residue was diluted with water (25 mL) andextracted with diethyl ether (1×15 mL). The aqueous layer was acidifiedto pH=1 with a 2N aqueous hydrochloric acid solution, and extracted withchloroform (3×25 mL). The combined organic layers were washed with water(1×25 mL) and a saturated aqueous sodium chloride solution (3×25 mL),dried over magnesium sulfate, filtered, and concentrated in vacuo toafford3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (426.7 mg, 65%) as a white solid: mp 122-123° C.; EI-HRMS m/e calcdfor C₁₆H₁₉F₃O₄S (M⁺) 364.0956 found 364.0956.

[0529] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (73 mg, 0.2 mmol) and triphenylphosphine (79 mg, 0.3 mmol) inmethylene chloride (5.0 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (60.5 mg, 0.34 mmol). After the complete addition ofN-bromosuccinimide, the reaction mixture was allowed to warm to 25° C.over 30 min. The reaction mixture was then treated with 2-aminopyridine(28.2 mg, 0.3 mmol) and pyridine (1 drop). The resulting reactionmixture was stirred at 25° C. for 48 h. The reaction mixture was thendiluted with methylene chloride (50 mL). The organic layer was washedwith water (1×50 mL) and a saturated aqueous sodium chloride solution(2×25 mL), dried over magnesium sulfate and sodium sulfate, filtered,and concentrated in vacuo. High pressure liquid chromatography(Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 50/50 heptane/ethylacetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide(54.2 mg, 61.5%) as a white solid: mp 86-89° C.; EI-HRMS m/e calcd forC₂₁H₂₃F₃N₂O₃S (M⁺) 440.1383, found 440.1381.

EXAMPLE 913-Cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide

[0530]

[0531] A solution of3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid(prepared as in Example 87A, 1.52 g, 5.0 mmol) in N,N-dimethylformamide(10 mL) was treated with sodium methanethiolate (593 mg, 7.5 mmol). Thereaction mixture was then heated to 100-110° C. for 14 h. At this time,the reaction was cooled to 25° C. and poured onto a 1N aqueoushydrochloric acid solution (25 mL) and extracted into ethyl acetate(3×25 mL) and diethyl ether (1×25 mL). The combined organic layers werethen washed with water (1×50 mL) and a saturated aqueous sodium chloridesolution (3×75 mL), dried over magnesium sulfate and sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (1.37 g, 82.4%) as a pale yellow oil: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1057.

[0532] A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (188 mg, 0.42 mmol) and3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (94 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL) was treated withN,N-diisopropylethylamine (150 μL, 0.85 mmol) and 2-aminothiazole (42.5mg, 0.42 mmol). The mixture was stirred at 25° C. for 48 h. At thistime, the reaction mixture was poured into cold water (25 mL) containinga 1N aqueous hydrochloric acid solution (50 mL) and extracted into ethylacetate (2×75 mL) and diethyl ether (1×25 mL). The combined organiclayers were then washed with water (2×75 mL) and a saturated aqueoussodium chloride solution (3×75 mL), dried over magnesium sulfate andsodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethylacetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide(50.5 mg, 43.1%) as a clear oil: FAB-HRMS m/e calcd forC₁₉H₂₁F₃N₂OS₂(M+H)⁺415.1125, found 415.1123.

EXAMPLE 922-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0533]

[0534] A solution of aluminum chloride (34.8 g, 261.4 mmol) inchloroform (120 mL) under argon was cooled to 0° C. and then treateddropwise with a solution of ethyl oxalyl chloride (18.7 mL, 167.5 mmol)in chloroform (120 mL). The reaction mixture was stirred at 0° C. for 30min and then treated dropwise with a solution of 2-chlorothioanisole(25.0 g, 156.5 mmol) in chloroform (120 mL). The resulting reactionmixture turned red in color. The reaction mixture was allowed to warm to25° C. where it was stirred for an additional 3.5 h. The reactionmixture was then slowly quenched with water (500 mL), and upon additionof the water, the reaction mixture turned yellow in color. The resultingsolution was then extracted with chloroform (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 80/20 hexanes/ethyl acetate) afforded(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (31.37 g,77%) as a yellow oil.

[0535] A solution of iodomethylcyclopentane (129.38 g, 0.616 mol) andtriphenylphosphine (161.54 g, 0.616 mol) in acetonitrile (308 mL) washeated under reflux for 9 d. The reaction mixture was allowed to cool to25° C. and then concentrated in vacuo to provide a solid. The solid wastriturated with diethyl ether and then filtered. The solid was washedwell with diethyl ether until the washings showed the absence ofiodomethylcyclopentane and triphenylphosphine by thin layerchromatography. The resulting solid was allowed to air dry to affordcyclopentylmethyl triphenylphosphonium iodide (266.92 g, 92%) as a lightyellow solid: mp 195-198° C.; FAB-HRMS m/e calcd for C₂₄H₂₆P(M+H)⁺345.1772, found 345.1784.

[0536] A suspension of cyclopentylmethyl triphenylphosphine iodide (725mg, 1.53 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and thentreated with a 1.0M solution of sodium bis(trimethylsilyl)amide intetrahydrofuran (2.14 mL, 2.14 mmol). The resulting red reaction mixturewas stirred at 0° C. for 45 minutes and then slowly treated with asolution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethylester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reactionmixture was warmed to 25° C. where it was stirred for 20 h. The reactionmixture was then diluted with water (50 mL) and extracted with diethylether (3×25 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(Flash 12M, Silica, 80/20 hexanes/ethyl acetate) afforded2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (267 mg, 60%) as a yellow oil consisting of a 2:1 mixture of(E):(Z) isomers. The isomeric mixture was used without furtherseparation and characterization.

[0537] A solution of the isomeric mixture of2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (100 mg, 0.31 mmol) in methylene chloride (5 mL) was cooled to 0°C. and then treated with 3-chloroperoxybenzoic acid (80% grade, 157 mg,0.729 mmol). The reaction mixture was stirred at 0° C. for 3.5 h andthen diluted with methylene chloride (25 mL). The organic phase waswashed with a saturated aqueous sodium carbonate solution (2×10 mL) anda saturated aqueous sodium chloride solution (2×10 mL). The organiclayer was dried over sodium sulfate, filtered, and concentrated invacuo. Biotage chromatography (Flash 12M, Silica, 80/20 hexanes/ethylacetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (95 mg, 86%) as a colorless oil consisting of a 2:1 mixture of(E):(Z) isomers. The isomeric mixture was used without furtherseparation and characterization.

[0538] A solution of the isomeric mixture of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (1.04 g, 2.91 mmol) and nickel chloride hexahydrate (69 mg, 0.29mmol) in methanol (25 mL) was slowly treated with sodium borohydride(221 mg, 5.83 mmol) in small portions. If necessary, an ice bath wasused to keep the temperature at 20° C. The initial green solution turnedblack in color, and a fine precipitate formed after addition of thesodium borohydride. The reaction mixture was then stirred at 25° C. for1.5 h. The reaction mixture was then filtered through celite and washedwith methanol. The filtrate and washings were combined and concentratedin vacuo to reduce the volume. The residual solution was then dilutedwith water (15 mL) and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 75/25 hexanes/ethyl acetate) afforded a mixture of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acidmethyl ester and2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethylester (937 mg, transesterification occurred under the reactionconditions) as a clear colorless oil. This mixture was used withoutfurther separation and characterization.

[0539] The mixture of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acidmethyl ester and2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethylester (937 mg) was dissolved in ethanol (30 mL). This solution was thentreated with a solution of potassium hydroxide (733 mg, 13.1 mmol) inwater (7 mL). The resulting yellow solution was stirred at 25° C. for 3h and then concentrated in vacuo to remove ethanol. The aqueous residuewas treated with a 1N aqueous hydrochloric acid solution until the pH=2.The product was then extracted into methylene chloride (3×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (787mg, 82% for two steps) as a white solid: mp 123.9-126.2° C.; FAB-HRMSm/e calcd for C₁₅H₁₉ClO₄S (M+H)⁺331.0771, found 331.0776.

[0540] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it became homogeneous. The resulting light purplereaction mixture was then treated with2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min andthen allowed to warm to 25° C. where it was stirred for 30 min. Thereaction mixture was then treated with 2-aminopyridine (85 mg, 0.91mmol) and pyridine (0.088 mL, 1.09 mmol), and then the reaction mixturewas stirred at 25° C. for 16 h. The reaction was then diluted with water(10 mL) and then extracted with methylene chloride (3×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 60/40 hexanes/ethyl acetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide(210 mg, 85%) as a colorless oil: EI-HRMS m/e calcd for C₂₀H₂₃N₂O₃SCl(M⁺) 406.1118, found 406.1120.

EXAMPLE 93N-(5-Bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

[0541]

[0542] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for20 min and then warmed to 25° C. where it was stirred for 30 min. Aftersuch time, the reaction mixture was treated with 2-amino-5-bromopyridine(157 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and reactionmixture was stirred at 25° C. for 16 h. The reaction was then dilutedwith water (10 mL) and then extracted with methylene chloride (3×15 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 70/30 hexanes/ethyl acetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-bromo-pyridin-2-yl)-propionamide(245 mg, 83%) as a white foam: EI-HRMS m/e calcd for C₂₀H₂₂Br ClN₂O₃S(M⁺) 484.0223, found 484.0222.

EXAMPLE 94N-(5-Chloro-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

[0543]

[0544] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for20 min and then warmed to 25° C. where it was stirred for 30 min. Aftersuch time, the reaction mixture was treated with2-amino-5-chloropyridine (117 mg, 0.91 mmol) and pyridine (0.088 mL,1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. Thereaction was then diluted with water (10 mL) and then extracted withmethylene chloride (3×15 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethylacetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-chloro-pyridin-2-yl)-propionamide(110 mg, 41%) as a yellow foam: EI-HRMS m/e calcd for C₂₀H₂₂ Cl₂N₂O₃S(M⁺) 440.0728, found 440.0728.

EXAMPLE 95 2-(3-Chlor-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

[0545]

[0546] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for20 min and then warmed to 25° C. where it was stirred for 30 min. Aftersuch time, the reaction mixture was treated with2-amino-5-trifluoromethyl-pyridine (147 mg, 0.91 mmol) and pyridine(0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C.for 16 h. The reaction was then diluted with water (10 mL) and thenextracted with methylene chloride (3×15 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40hexanes/ethyl acetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide(122 mg, 43%) as a white foam: EI-HRMS m/e calcd for C₂₀H₂₂ ClF₃N₂O₃S(M⁺) 474.0992, found 474.0990.

EXAMPLE 96{2-[2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester

[0547]

[0548] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for20 min and then warmed to 25° C. where it was stirred for 30 min. Aftersuch time, the reaction mixture was treated with2-(amino-thiazol-4-yl)-oxo-acetic acid ethyl ester (182 mg, 0.91 mmol)and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirredat 25° C. for 16 h. The reaction was then diluted with water (10 mL) andthen extracted with methylene chloride (3×15 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25hexanes/ethyl acetate) afforded{2-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester (208 mg, 67%) as a clear colorless oil: EI-HRMS m/ecalcd for C₂₂H₂₅ClN₂O₆S₂ (M⁺) 513.0921, found 513.0919.

EXAMPLE 972(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0549]

[0550] A mixture of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 92, 6.07 g, 18.35 mmol),(R)-(+)-4-benzyl-2-oxazolidinone (2.83 g, 15.96 mmol), and triethylamine(6.68 mL, 47.71 mmol) in toluene (50 mL) was heated at 80° C. underargon until a homogeneous solution was obtained. The reaction mixturewas then treated with trimethylacetyl chloride (3.55 mL, 28.81 mmol) intoluene (10 mL), and the reaction became yellow in color and aprecipitate formed. The reaction mixture was then heated at 80° C. for36 h. The reaction was cooled to 25° C. and then the toluene was removedin vacuo. The residue was diluted with ethyl acetate (150 mL). Theorganic layer was washed sequentially with a 1N aqueous hydrochloricsolution (1×100 mL), a 10% aqueous sodium carbonate solution (1×100 mL),and a saturated aqueous sodium chloride solution (1×100 mL). The organiclayer was then dried over magnesium sulfate, filtered, and concentratedin vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,90/5/5 methylene chloride/hexanes/ethyl acetate) afforded two products:(1)4(R)-benzyl-3-[2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one(2.08 g, 23%) as a white foam: [α]²³ ₅₈₉=+10.4° (c=0.144, chloroform);FAB-HRMS m/e calcd for C₂₅H₂₈ClNO₅S (M+H)⁺490.1455, found 490.1457; and(2)4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one(2.20 g, 25%) as a white foam: [α]²³ ₅₈₉=−93.9° (c=0.165, chloroform);FAB-HRMS m/e calcd for C₂₅H₂₈ClNO₅S (M+H)⁺490.1455, found 490.1443.

[0551] A solution of lithium hydroxide (215 mg, 9.0 mmol) in water (2.8mL) was treated with a 30% aqueous hydrogen peroxide solution (2.0 mL,18 mmol). This freshly prepared lithium hydroperoxide solution was thencooled to 0° C. and then slowly added to a cooled (0° C.) solution of4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one(2.20 g, 4.5 mmol) in tetrahydrofuran (18 mL) and water (5.8 mL). After1.5 h at 0° C., the reaction was quenched with a 1.5N aqueous sodiumsulfite solution (25 mL) and was diluted with water (150 mL). Theaqueous layer was extracted with diethyl ether (3×50 mL). The aqueouslayer was then acidified with a 1N aqueous hydrochloric acid solution topH=2 and extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25hexanes/ethyl acetate with 1% acetic acid) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(1.26 g, 85%) as a white solid: mp 106.1-108.8° C.; [α]²³ ₅₈₉=−43.0°(c=0.172, chloroform); EI-HRMS m/e calcd for C₁₅H₁₉ClO₄S (M⁺) 330.0692,found 330.0690.

[0552] A solution of triphenylphosphine (248 mg, 0.94 mmol) in methylenechloride (9 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (190 mg, 1.07 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(208 mg, 0.63 mmol). The reaction mixture was stirred at 0° C. for 20min and then warmed to 25° C. where it was stirred for 30 min. Aftersuch time, the reaction mixture was treated with 2-aminothiazole (95 mg,0.94 mmol) and pyridine (0.092 mL, 1.13 mmol), and the reaction mixturewas stirred at 25° C. for 16 h. The reaction was then diluted with water(10 mL) and then extracted with methylene chloride (3×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide(210 mg, 81%) as a white foam: [α]²³ ₅₈₉ =−54.3° (c=0.081, chloroform);EI-HRMS m/e calcd for C₁₈H₂₁ClN₂O₃S₂ (M⁺) 412.0682, found 412.0679.

EXAMPLE 982(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0553]

[0554] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 97, 200 mg, 0.61 mmol). The reaction mixture wasstirred at 0° C. for 20 min and then warmed to 25° C. where it wasstirred for 30 min. After such time, the reaction mixture was treatedwith 2-aminopyridine (85 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09mmol), and the reaction mixture was stirred at 25° C. for 16 h. Thereaction was then diluted with water (10 mL) and then extracted withmethylene chloride (3×15 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide(202 mg, 81.5%) as a white foam: [α]²³ ₅₈₉=−41.8° (c=0.098, chloroform);EI-HRMS m/e calcd for C₂₀H₂₃ClN₂O₃S (M⁺) 406.1118, found 406.1119.

EXAMPLE 99N-(5-Bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

[0555]

[0556] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 97, 200 mg, 0.61 mmol). The reaction mixture wasstirred at 0° C. for 20 min and then warmed to 25° C. where it wasstirred for 30 min. After such time, the reaction mixture was treatedwith 2-aminopyridine (85 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09mmol), and the reaction mixture was stirred at 25° C. for 16 h. Thereaction was then diluted with water (10 mL) and then extracted withmethylene chloride (3×15 mL). The combined organic layers were thendried over sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) affordedN-(5-bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide(222 mg, 76%) as an off-white foam: [α]²³ ₅₈₉=−48.6° (c=0.105,chloroform); EI-HRMS m/e calcd for C₂₀H₂₂BrClN₂O₃S (M⁺) 484.0223, found484.0223.

EXAMPLE 100N-(5-Cyano-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide

[0557]

[0558] A solution of nickel(II) bromide (253 mg, 1.16 mmol),triphenylphosphine (1.15 g, 4.39 mmol), and zinc powder (113 mg, 1.73mmol) in acetonitrile (11 mL) was stirred under argon at 60° C. for 1 h.The reaction turned dark brown in color. After such time, the reactionmixture was treated with sodium cyanide (578 mg, 11.8 mmol) and2-amino-5-bromopyridine (2.00 g, 11.6 mmol), and the reaction mixturewas stirred at 60° C. for 16 h. The reaction mixture was then cooled to25° C., diluted with ethyl acetate (50 mL), and then filtered throughcelite. The filtrate was concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded6-amino-nicotinonitrile (577 mg, 42%) as a white solid: mp 156.8-158.5°C.; EI-HRMS m/e calcd for C₆H₅N₃ (M⁺) 119.0483, found 119.0480.

[0559] A solution of triphenylphosphine (1.23 g, 4.70 mmol) in methylenechloride (26 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (948 mg, 5.33 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as inExample 38A, 900 mg, 3.13 mmol). The reaction mixture was stirred at 0°C. for 20 min and then warmed to 25° C. where it stirred for 30 min.After such time, the reaction mixture was treated with6-amino-nicotinonitrile (560 mg, 4.70 mmol) and pyridine (0.46 mL, 5.64mmol), and the reaction mixture was stirred at 25° C. for 16 h. Thereaction was then diluted with water (25 mL) and then extracted withmethylene chloride (3×25 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethylacetate) affordedN-(5-cyano-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide(882 mg, 73%) as a pink foam: EI-HRMS m/e calcd for C₂₀H₁₉Cl₂N₃O (M⁺)387.0905, found 387.0905.

EXAMPLE 1013-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

[0560]

[0561] A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionicacid (prepared as in Example 54A, 200 mg, 0.69 mmol) in methylenechloride (10 mL) and one drop of N,N-dimethylformamide was cooled to 0°C. and then treated with a 2.0M solution of oxalyl chloride in methylenechloride (0.42 mL, 0.84 mmol). Gas evolution began immediately. Thereaction mixture was allowed to warm slowly to 25° C. where it wasstirred for 30 min. After this time, the reaction mixture was treatedwith a solution of N,N-diisopropylethylamine (0.24 mL, 1.39 mmol) and5-trifluoromethyl-2-aminopyridine (150 mg, 0.905 mmol) intetrahydrofuran (4 mL) in one portion. The resulting reaction mixturewas stirred for 16 h at 25° C. After such time, the reaction was dilutedwith water (15 mL) and was extracted with methylene chloride (3×15 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 90/10 hexanes/ethyl acetate) afforded the3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide(77 mg, 26%) as a white solid: mp 113.8-117.5° C.; EI-HRMS m/e calcd forC₂₀H₁₉Cl₂F₃N₂O (M⁺) 430.0826, found 430.0835.

EXAMPLE 1026-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid

[0562]

[0563] A solution of6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid methyl ester (prepared as in Example 45, 188 mg, 0.45 mmol) intetrahydrofuran (3 mL) was treated with a 3N aqueous hydrochloric acidsolution (3 mL). The resulting reaction mixture was heated under refluxat 60° C. for 4 h. After such time, the reaction was cooled to 25° C.,diluted with water (5 mL), and then extracted with ethyl acetate (3×20mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate with 1% acetic acid)afforded6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid (8 mg, 4%) as a white solid: [α]²³ ₅₈₉=−41.4° (c=0.099,chloroform); FAB-HRMS m/e calcd for C₂₀H₂₀Cl₂N₂O₃ (M+H)⁺407.0930, found407.0928.

EXAMPLE 1036-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide

[0564]

[0565] A solution of6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid(prepared as in Example 46, 125 mg, 0.31 mmol),N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), andbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(142 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL) at 25° C. wastreated dropwise with a 2.0M solution of methylamine in tetrahydrofuran(0.16 mL, 0.32 mmol). The resulting reaction mixture was stirred at 25°C. for 16 h. The reaction mixture was then diluted with water (10 mL)and extracted with ethyl acetate (3×10 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50hexanes/ethyl acetate) afforded6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide(83 mg, 64%) as white solid: mp 229.1-231.7° C.; FAB-HRMS m/e calcd forC₂₁H₂₃Cl₂N₃O₂ (M+H)⁺420.1245, found 420.1247.

EXAMPLE 1043-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide

[0566]

[0567] A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionicacid (prepared as in Example 38 Å, 100 mg, 0.35 mmol) in methylenechloride (5 mL) and one drop of N,N-dimethylformamide was cooled to 0°C. and then treated with a 2.0M solution of oxalyl chloride in methylenechloride (0.20 mL, 0.39 mmol). Gas evolution began immediately. Thereaction mixture was stirred for 30 min at 0° C. After this time, thereaction mixture was treated with a solution ofN,N-diisopropylethylamine (0.15 mL, 0.84 mmol) and 2-aminopyrazine (69mg, 0.73 mmol) in tetrahydrofuran (4 mL) in one portion. The resultingreaction mixture was stirred for 16 h at 25° C. The reaction mixture wasthen diluted with water (10 mL) and extracted with methylene chloride(3×15 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide (38mg, 30%) as a yellow solid: mp 46.5-51.3° C.; EI-HRMS m/e calcd forC₁₈H₁₉Cl₂N₃O (M⁺) 363.0905, found 363.0907.

EXAMPLE 105N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide

[0568]

[0569] A solution of triphenylphosphine (411 mg, 1.57 mmol) in methylenechloride (15 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (316 mg, 1.78 mmol). The reaction mixture was stirredat 0° C. until it was completely dissolved and became light purple incolor. The reaction mixture was then treated with3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as inExample 54 Å, 300 mg, 1.05 mmol). The reaction mixture was stirred at 0°C. for 20 min and then warmed to 25° C. where it was stirred for 30 min.After such time, the reaction mixture was treated with2-amino-5-bromopyridine (271 mg, 1.57 mmol) and pyridine (0.15 mL, 1.88mmol). The resulting reaction mixture was stirred at 25° C. for 16 h.The reaction was then diluted with water (10 mL) and extracted withmethylene chloride (3×15 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethylacetate) affordedN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide(448 mg, 97%) as a white solid: mp 107.3-109.9° C.; [α]²³ ₅₈₉=−66.7°(c=0.084, chloroform); EI-HRMS m/e calcd for C₁₉H₁₉BrCl₂N₂O (M⁺)440.0058, found 440.0056.

EXAMPLE 1063-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)

[0570]

[0571] A solution of6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid methyl ester (prepared as in Example 45, 398 mg, 0.95 mmol) indiethyl ether (30 mL) was cooled to 0° C. and then treated with lithiumaluminum hydride (54 mg, 1.4 mmol) in one portion. There was immediategas evolution. The reaction mixture was allowed to slowly warm to 25° C.and was stirred at 25° C. 16 h. After such time, the reaction mixturewas diluted with water (10 mL) and then extracted with ethyl acetate(3×15 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)propionamide (131 mg, 35%) as a white foam: FAB-HRMS m/e calcd forC₂₀H₂₂Cl₂N₂O₂ (M+H)⁺392.1058, found 392.1062.

EXAMPLE 1073-Cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0572]

[0573] A mixture of magnesium metal (4.81 g, 200 mmol) and drytetrahydrofuran (10 mL) under argon was treated with a solution of1,2-dibromoethane (0.94 g, 5 mmol) in dry tetrahydrofuran (5 mL). Theresulting reaction mixture was stirred for 10 min to activate themagnesium metal. The reaction mixture was then treated dropwise with asolution of cycloheptyl bromide (17.7 g, 100 mmol) in drytetrahydrofuran (30 mL), one-fifth portion over a period of 5 min. Theresulting reaction mixture was stirred for 5-10 min to initiate theexothermic reaction. The remaining portion of the cycloheptyl bromidesolution was then added dropwise while controlling the insidetemperature below 50° C. After complete addition, the solution wasstirred for 1 h and then diluted with dry tetrahydrofuran (80 mL). In aseparate reaction flask, a mixture of lithium chloride (8.48 g, 200mmol, predried at 130° C. under high vacuum for 3 h) and copper(I)cyanide (8.96 g, 100 mmol) in dry tetrahydrofuran (110 mL) was stirredat 25° C. under argon for 10 min to obtain a clear solution. Thereaction mixture was cooled to −70° C. and then slowly treated with thefreshly prepared cycloheptylmagnesium bromide. After the addition, thereaction mixture was allowed to warm to −10° C. where it was stirred for5 min. The resulting reaction mixture was again cooled back to −70° C.and then treated with methyl propiolate (7.57 g, 90 mmol). The reactionmixture was stirred for 15 h at −70° C. to −50° C. and then slowlytreated with a solution of iodine (34.3 g, 135 mmol) in drytetrahydrofuran (30 mL) while maintaining the temperature at −70° C. to−60° C. After addition of the iodine solution, the cooling bath wasremoved, and the reaction mixture was allowed to warm to 25° C. where itwas stirred for 2 h. The reaction mixture was then poured into asolution consisting of a saturated aqueous ammonium chloride solution(400 mL) and ammonium hydroxide (100 mL), and the organic compound wasextracted into ethyl acetate (3×200 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×400 mL) and a saturated aqueous sodium chloride solution(1×400 mL). The organic layer was then dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 20/1 to 10/1 hexanes/diethyl ether)afforded (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (17.86 g,64%) as a colorless oil: EI-HRMS m/e calcd for C₁₁H₁₇IO₂ (M⁺) 308.0273,found 308.0273.

[0574] A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, −325 mesh) anddry tetrahydrofuran (3 mL) under argon was treated with1,2-dibromoethane (0.38 g, 2 mmol). The zinc suspension was then heatedwith a heat gun to ebullition, allowed to cool, and heated again. Thisprocess was repeated three times to make sure the zinc dust wasactivated. The activated zinc dust suspension was then treated withtrimethylsilyl chloride (220 mg, 2 mmol), and the suspension was stirredfor 15 min at 25° C. The reaction mixture was then treated dropwise witha solution of (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (6.16g, 20 mmol) in dry tetrahydrofuran (5 mL) over 10 min. The reactionmixture was then stirred at 40-45° C. for 1 h and then stirred overnightat 25° C. The reaction mixture was then diluted with dry tetrahydrofuran(10 mL), and the stirring was stopped to allow the excess zinc dust tosettle down (˜2 h). In a separate reaction flask,bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) andtriphenylphosphine (520 mg, 2 mmol) in dry tetrahydrofuran (25 mL) wasstirred at 25° C. under argon for 10 min and then treated with4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly preparedzinc compound in tetrahydrofuran. The resulting brick red solution washeated at 50° C. for 24 h. The reaction mixture was cooled to 25° C. andthen poured into a saturated aqueous ammonium chloride solution (150mL), and the organic compound was extracted into ethyl acetate (3×150mL). The combined organic extracts were washed with a saturated aqueoussodium chloride solution (1×300 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate)afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acidmethyl ester (6.01 g, 99%) as a viscous yellow oil: EI-HRMS m/e calcdfor C₁₈H₂₄O₄S (M⁺) 336.1395, found 336.1395.

[0575] A solution of nickel(II) chloride hexahydrate (7.8 mg, 0.033mmol) and (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acidmethyl ester (111 mg, 0.33 mmol) in methanol (3 mL) was cooled to 0° C.and then treated with sodium borohydride (25 mg, 0.66 mmol) in twoportions. After the addition, the black reaction mixture was stirred for15 min at 0° C. and then allowed to warm to 25° C. where it was stirredfor 15 h. The black solid was filtered using filter paper and washedwith methanol. The combined solvents were concentrated in vacuo, and theresidue was diluted with water (25 mL) and ethyl acetate (25 mL). Thetwo layers were separated, and the aqueous layer was extracted withethyl acetate (1×15 mL). The combined organic extracts were washed witha saturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford racemic 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acidmethyl ester (101 mg, 91%) as a colorless oil: EI-HRMS m/e calcd forC₁₈H₂₆O₄S (M⁺) 338.1552, found 338.1555.

[0576] A solution of3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester(95 mg, 0.28 mmol) in ethanol (2 mL) was treated with a 1N aqueoussodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C.for 15 h, at which time, thin layer chromatography analysis of thereaction mixture indicated the absence of starting material. Thereaction mixture was concentrated in vacuo to remove ethanol. Theresidue was diluted with water (10 mL) and extracted with diethyl ether(1×20 mL) to remove any neutral impurities. The aqueous layer was thenacidified with a 1N aqueous hydrochloric acid solution, and theresulting acid was extracted into ethyl acetate (2×15 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×50 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to afford3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (78 mg, 86%)as a white solid: EI-HRMS m/e calcd for C₁₇H₂₄O₄S (M+H)⁺325.1474, found325.1478.

[0577] A solution of triphenylphosphine (116 mg, 0.44 mmol) in methylenechloride (2 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (78 mg, 0.44 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (72 mg, 0.22mmol) in methylene chloride (2 mL). The clear solution was stirred for10 min at 0° C. and then allowed to warm to 25° C. where it was stirredfor 1.5 h. The reaction mixture was then treated with 2-aminothiazole(66 mg, 0.66 mmol), and the resulting suspension was stirred for 20 h at25° C. The reaction mixture was then concentrated in vacuo to removemethylene chloride, and the residue was diluted with ethyl acetate (30mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×10 mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×20 mL) and a saturatedaqueous sodium chloride solution (1×30 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate)afforded3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(68 mg, 76%) as an amorphous solid: EI-HRMS m/e calcd for C₂₀H₂₆N₂O₃S₂(M⁺) 406.1426, found 406.1424.

EXAMPLE 1083-Cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0578]

[0579] A mixture of zinc dust (16.34 g, 250 mmol, Aldrich, -325 mesh)and dry tetrahydrofuran (6 mL) under argon was treated with1,2-dibromoethane (0.94 g, 5 mmol). The zinc suspension was then heatedwith a heat gun to ebullition, allowed to cool, and heated again. Thisprocess was repeated three times to make sure the zinc dust wasactivated. The activated zinc dust suspension was then treated withtrimethylsilyl chloride (0.54 g, 5 mmol), and the suspension was stirredfor 15 min at 25° C. The reaction mixture was then treated dropwise witha solution of cyclohexyl iodide (21 g, 100 mmol) in dry tetrahydrofuran(30 mL) over 15 min. During the addition, the temperature rose to 60° C.The reaction mixture was then stirred for 3 h at 40-45° C. The reactionmixture was then cooled to 25° C. and diluted with dry tetrahydrofuran(60 mL). The stirring was stopped to allow the excess zinc dust tosettle down (3 h). In a separate reaction flask, a mixture of lithiumchloride (8.48 g, 200 mmol, predried at 130° C. under high vacuum for 3h) and copper(I) cyanide (8.95 g, 100 mmol) in dry tetrahydrofuran (110mL) was stirred for 10 min at 25° C. to obtain a clear solution. Thereaction mixture was cooled to −70° C. and then slowly treated with thefreshly prepared zinc solution using a syringe. After the addition, thereaction mixture was allowed to warm to 0° C. where it was stirred for 5min. The reaction mixture was again cooled back to −70° C. and thenslowly treated with methyl propiolate (7.56 g, 90 mmol). The resultingreaction mixture was stirred for 15 h at −70° C. to −50° C. and thenslowly treated with a solution of iodine (34.26 g, 135 mmol) in drytetrahydrofuran (30 mL) while maintaining the temperature at −70° C. to−60° C. After addition of the iodine solution, the cooling bath wasremoved, and the reaction mixture was allowed to warm to 25° C. where itwas stirred for 2 h. The reaction mixture was then poured into asolution consisting of a saturated aqueous ammonium chloride solution(400 mL) and ammonium hydroxide (100 mL), and the organic compound wasextracted into ethyl acetate (3×250 mL). The combined organic extractswere successively washed with a saturated aqueous sodium thiosulfatesolution (1×500 mL) and a saturated aqueous sodium chloride solution(1×500 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 9/1 hexanes/diethyl ether) afforded(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (26.3 g, 99%) as alight pink oil: EI-HRMS m/e calcd for C₁₀H₁₅IO₂ (M⁺) 294.0117, found294.0114.

[0580] A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, -325 mesh) anddry tetrahydrofuran (3 mL) under argon was treated with1,2-dibromoethane (0.37 g, 2 mmol). The zinc suspension was then heatedwith a heat gun to ebullition, allowed to cool, and heated again. Thisprocess was repeated three times to make sure the zinc dust wasactivated. The activated zinc dust suspension was then treated withtrimethylsilyl chloride (217 mg, 2 mmol), and the suspension was stirredfor 15 min at 25° C. The reaction mixture was then treated dropwise witha solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (5.88 g,20 mmol) in dry tetrahydrofuran (5 mL) over 5 min. During the addition,the temperature rose to 50° C. The reaction mixture was then stirred at40-45° C. for 1 h and then stirred overnight at 25° C. The reactionmixture was then diluted with dry tetrahydrofuran (10 mL), and thestirring was stopped to allow the excess zinc dust to settle down (˜2h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)(270 mg, 0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in drytetrahydrofuran (25 mL) was stirred at 25° C. under argon for 10 min andthen treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and thefreshly prepared zinc compound in tetrahydrofuran. The resulting brickred solution was heated at 50° C. for 24 h, at which time, thin layerchromatography analysis of the reaction mixture indicated the absence ofstarting material. The reaction mixture was cooled to 25° C. and thenpoured into a saturated aqueous ammonium chloride solution (150 mL), andthe organic compound was extracted into ethyl acetate (3×100 mL). Thecombined organic extracts were washed with a saturated aqueous sodiumchloride solution (1×200 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 3/2 hexanes/ethyl acetate) afforded(E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester(5.79 g, 99%) as a low melting white solid: EI-HRMS m/e calcd forC₁₇H₂₂O₄S (M⁺) 322.1238, found 322.1236.

[0581] A solution of nickel(II) chloride hexahydrate (157 mg, 0.66 mmol)and (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methylester (1.07 g, 3.31 mmol) in methanol (30 mL) was cooled to 0° C. andthen treated with sodium borohydride (380 mg, 10 mmol) in four portions.After the addition, the black reaction mixture was stirred for 15 min at0° C. and then allowed to warm to 25° C. where it was stirred for 15 h.The black solid was filtered using filter paper and washed withmethanol. The combined solvents were concentrated in vacuo, and theresidue was diluted with water (50 mL) and ethyl acetate (50 mL). Thetwo layers were separated, and the aqueous layer was extracted withethyl acetate (1×25 mL). The combined organic extracts were washed witha saturated aqueous sodium chloride solution (1×50 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford racemic 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acidmethyl ester (1.04 g, 97%) as an amorphous white solid: EI-HRMS m/ecalcd for C₁₇H₂₄O₄S (M⁺) 324.1395, found 324.1395.

[0582] A solution of 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionicacid methyl ester (1.00 g, 3.08 mmol) in ethanol (15 mL) was treatedwith a 1N aqueous sodium hydroxide solution (6 mL). The solution washeated at 45-50° C. for 15 h, at which time, thin layer chromatographyanalysis of the mixture indicated the absence of starting material. Thereaction mixture was then concentrated in vacuo to remove ethanol, andthe residue was diluted with water (20 mL) and extracted with diethylether (1×40 mL) to remove any neutral impurities. The aqueous layer wasacidified with a 1N aqueous hydrochloric acid solution. The resultingacid was extracted into ethyl acetate (2×50 mL). The combined organiclayers were washed with a saturated aqueous sodium chloride solution(1×50 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (570 mg, 60%)as a white solid: mp 139-143° C.; EI-HRMS m/e calcd for C₁₆H₂₂O₄S (M⁺)310.1239, found 310.1241.

[0583] A solution of triphenylphosphine (416 mg, 1.58 mmol) in methylenechloride (8 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (281 mg, 1.58 mmol). The reaction mixture was stirredat 0° C. for 30 min and then treated with a solution of3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (290 mg, 0.93mmol) in methylene chloride (5 mL). The clear solution was stirred for15 min at 0° C. and then allowed to warm to 25° C. where it was stirredfor 1.5 h. The reaction mixture was then treated with 2-aminothiazole(233 mg, 2.32 mmol), and the resulting suspension was stirred for 20 hat 25° C. The reaction mixture was concentrated in vacuo to removemethylene chloride, and the residue was diluted with ethyl acetate (50mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(1×30 mL). The combined organic extracts were successively washed with asaturated aqueous sodium bicarbonate solution (1×50 mL) and a saturatedaqueous sodium chloride solution (1×50 mL), dried over anhydrousmagnesium sulfate, filtered, and, concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate)afforded3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(337 mg, 92%) as an amorphous solid: EI-HRMS m/e calcd for C₁₉H₂₄N₂O₃S₂(M⁺) 392.1228, found 392.1230.

EXAMPLE 109 3-Cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-yl-propionamide

[0584]

[0585] A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) inmethanol (50 mL) was treated with a catalytic amount of sulfuric acid.The reaction mixture was heated under reflux for 48 h. The reaction wasthen concentrated in vacuo. The residue was dissolved in methylenechloride (50 mL). The organic layer was washed with a saturated aqueoussodium bicarbonate solution (2×25 mL), water (1×50 mL), and a saturatedaqueous sodium chloride solution (1×50 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo togive (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a paleyellow solid: mp 29-30° C.; EI-HRMS m/e calcd for C₉H₉NO₄ (M⁺) 195.0531,found 195.0532.

[0586] A solution of freshly prepared lithium diisopropylamide (43.3 mLof a 0.3M stock solution, 12.99 mmol) cooled to −78° C. was treated with(3-nitro-phenyl)-acetic acid methyl ester (2.45 g, 12.56 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (32mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Atthis time, the reaction was treated with a solution ofiodomethylcyclopentane (2.78 g, 13.23 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.78 mL), and themixture was stirred at −78° C. for 3 h. The reaction was warmed to 25°C. and was stirred at 25° C. for 16 h. The reaction mixture was thenquenched by the dropwise addition of a saturated aqueous ammoniumchloride solution (25 mL) and was concentrated in vacuo. The residue wasdiluted with water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with a saturated aqueous lithiumchloride solution (2×25 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh 80/20 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (1.63 g,46.8%) as pale yellow oil: EI-HRMS m/e calcd for C₁₅H₁₉NO₄ (M⁺)277.1314, found 277.1317.

[0587] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acidmethyl ester (0.55 g, 2.0 mmol) in tetrahydrofuran/water (12 mL, 3:1)was treated with lithium hydroxide (185 mg, 4.40 mmol). The reaction wasstirred at 25° C. for 48 h. The tetrahydrofuran was then removed invacuo. The residue was diluted with water (25 mL) and extracted withether (1×20 mL). The aqueous layer was acidified to pH=2 with a 3Naqueous hydrochloric acid solution. The solution was extracted withmethylene chloride (3×25 mL). The combined organic layers were washedwith a saturated aqueous sodium chloride solution (2×25 mL), dried oversodium sulfate, filtered, and concentrated in vacuo to give3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid (0.48 g, 91.9%) as a tansolid: mp 95-99° C.; EI-HRMS m/e calcd for C₁₄H₁₇NO₄ (M⁺) 263.1157,found 263.1156.

[0588] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid(432 mg, 1.64 mmol) in methylene chloride (16 mL) was cooled to 0° C.and then treated with a 2.0M solution of oxalyl chloride in methylenechloride (0.90 mL, 1.80 mmol) and a few drops of N,N-dimethylformamide.The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for1.2 h. The reaction mixture was then treated with a solution of2-aminothiazole (361.4 mg, 3.61 mmol) and N,N-diisopropylethylamine(0.70 mL, 3.93 mmol) in tetrahydrofuran (16 mL). The reaction mixturewas stirred at 25° C. for 6 h. At this time, the reaction wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh 70/30 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl-propionamide (409.3 mg,72.2%) as a tan solid: mp 171-174° C.; EI-HRMS m/e calcd for C₁₇H₁₉N₃O₃S(M⁺) 345.1147, found 345.1153.

EXAMPLE 1103-Cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide

[0589]

[0590] A solution of freshly prepared lithium diisopropylamide (23 mL ofa 0.3 1M stock solution, 7.13 mmol) cooled to −78° C. was treated with(3-methoxy-phenyl)-acetic acid methyl ester (1.07 g, 5.94 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone(14.8 mL, 3:1). The resulting solution was stirred at −78° C. for 45min. At this time, the reaction was treated with a solution ofiodomethylcyclopentane (1.37 g, 6.53 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). Thereaction mixture was stirred at −78° C. for 3 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 16 h. At this time, thereaction was quenched by the dropwise addition of a saturated aqueousammonium chloride solution. This solution was diluted with water (100mL) and extracted into ethyl acetate (3×50 mL). The combined organiclayers were washed with a saturated aqueous lithium chloride solution(1×75 mL), dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester (1.39 g,89.1%) as a clear oil: EI-HRMS m/e calcd for C₁₆H₂₂O₃ (M⁺) 262.1568,found 262.1561.

[0591] A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acidmethyl ester (1.39 g, 5.29 mmol) in tetrahydrofuran/water/methanol (13.2mL, 3:1:1) at 25° C. was treated with a 2N aqueous sodium hydroxidesolution (3.97 mL, 7.94 mmol). The reaction was stirred at 25° C. for 48h. At this time, the reaction mixture was poured into water (50 mL) andextracted with chloroform (3×25 mL). The aqueous layer was acidified topH=1 with a 1N aqueous hydrochloric acid solution. The aqueous layer wasextracted with a solution of chloroform/methanol (9:1). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 70/30 hexanes/ethyl acetate with glacial acetic acid)afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid (1.05 g,79.8%) as a clear wax: EI-HRMS m/e calcd for C₁₅H₂₀O₃(M⁺) 248.1412,found 248.1409.

[0592] A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid(500 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to 0° C. wastreated with a 2.0M solution of oxalyl chloride in methylene chloride(1.1 mL, 2.20 mmol) and a few drops of N,N-dimethylformamide. Thereaction mixture was stirred at 0° C. for 10 min then at 25° C. for 30min. The reaction mixture was then treated with 2-aminothiazole (444 mg,4.42 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.83 mmol) intetrahydrofuran (10.1 mL). This solution was stirred at 25° C. for 18 h.At this time, the reaction was concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethylacetate) afforded3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide (549mg,82.6%) as a white solid: mp 44-45° C.; EI-HRMS m/e calcd for C₁₈H₂₂N₂O₂S(M⁺) 330.1402 found 330.1398.

EXAMPLE 1113-Cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide

[0593]

[0594] A 1.0M solution of boron tribromide in methylene chloride (3.53mL, 3.53 mmol) at 25° C. was treated with a solution of3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide (preparedas in Example 110, 0.11 g, 0.35 mmol) in methylene chloride (3.5 mL).This solution was stirred at 25° C. for 1 h. At this time, the reactionwas cooled to 0° C. and treated with a dilute aqueous ammonium hydroxidesolution. This mixture was stirred at 0° C. for 15 min. At this time,the aqueous layer was separated from the organic layer. The aqueouslayer was extracted with chloroform (3×50 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide (50 mg,44.7%) as a white solid: mp 177-179° C.; EI-HRMS m/e calcd forC₁₇H₂₀N₂O₂S (M⁺) 316.1245 found 316.1244.

EXAMPLE 1123-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide

[0595]

[0596] A solution of freshly prepared lithium diisopropylamide (23 mL ofa 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with(4-trifluoromethoxy-phenyl)-acetic acid (0.74 g, 3.39 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Atthis time, the reaction was treated with a solution ofiodomethylcyclopentane (0.78 g, 3.73 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reactionmixture was stirred at −78° C. for 4 h. The reaction was then warmed to25° C. and was stirred at 25° C. for 18 h. The reaction mixture was thenquenched by the dropwise addition of saturated aqueous ammonium chloridesolution (10 mL). The resulting mixture was concentrated in vacuo toremove the excess solvent. The residue was diluted with water (100 mL)and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. Thissolution was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with a saturated aqueous lithium chloridesolution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-trifluoromethoxy-phenyl)-propionic acid (0.31 g,30.6%) as a tan solid: mp 62-64° C.; EI-HRMS m/e calcd forC₁₅H₁₇F₃O₃(M⁺) 302.1129 found 302.1131.

[0597] A solution of3-cyclopentyl-2-(4-trifluoromethoxy-phenyl)-propionic acid (0.16 g, 0.52mmol) in methylene chloride (5.3 mL) cooled to 0° C. was treated with a2.0M solution of oxalyl chloride in methylene chloride (0.29 mL, 0.58mmol) and a few drops of N,N-dimethylformamide. The reaction mixture wasstirred at 0° C. for 10 min and at 25° C. for 30 min. The reactionmixture was then treated with a solution of 2-aminothiazole (0.11 g,1.16 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.27 mmol) intetrahydrofuran (2.65 mL). The reaction mixture was stirred at 25° C.for 18 h. At this time, the reaction was concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh 80/20 hexanes/ethylacetate) afforded3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide(203.8 mg, 100%) as a white solid: mp 168-170° C.; EI-HRMS m/e calcd forC₁₈H₁₉F₃N₂O₂S (M⁺) 384.1119, found 384.1118.

EXAMPLE 1133-Cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide

[0598]

[0599] A solution of freshly prepared lithium diisopropylamide (58.5 mLof a 0.91M stock solution, 53.2 mmol) cooled to −78° C. was treated with(3,4-dimethoxy-phenyl)-acetic acid (4.97 g, 25.3 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3mL, 3:1). The resulting solution was stirred at −78° C. for 45 min andat 25° C. for 15 min. At this time, the reaction was cooled to 0° C. andwas treated with a solution of iodomethylcyclopentane (5.87 g, 27.8mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). Thereaction mixture was stirred at 0° C. for 30 min. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 18 h. The reactionmixture was then quenched by the dropwise addition of saturated aqueousammonium chloride solution (10 mL). The resulting mixture wasconcentrated in vacuo. The residue was diluted with water (100 mL) andacidified to pH=1 with a 1N aqueous hydrochloric acid solution. Thissolution was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with a saturated aqueous lithium chloridesolution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 70/30 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (4.5 g, 63.8%) asa yellow solid: mp 111-112° C.; EI-HRMS m/e calcd for C₁₆H₂₂O₄(M⁺)278.1518 found 278.1517.

[0600] A solution of 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionicacid (0.50 g, 1.79 mmol) in methylene chloride (17.9 mL) cooled to 0° C.was treated with a 2.0M solution of oxalyl chloride in methylenechloride (1.0 mL, 1.97 mmol) and a few drops of N,N-dimethylformamide.The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for30 min. The reaction mixture was then treated with a solution of2-aminothiazole (0.39 g, 3.95 mmol) and N,N-diisopropylethylamine (0.76mL, 4.3 mmol) in tetrahydrofuran (8.98 mL). The reaction mixture wasstirred at 25° C. for 18 h. At this time, the reaction was concentratedin vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 80/20hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide (665mg, 100%) as a pale yellow solid: mp 50-52° C.; EI-HRMS m/e calcd forC₁₉H₂₄N₂O₃S (M⁺) 360.1507, found 360.1516.

EXAMPLE 1143-Cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide

[0601]

[0602] A 1.0M solution of boron tribromide in methylene chloride (7.43mL, 7.43 mmol) at 25° C. was treated with a solution of3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide(prepared as in Example 113, 0.27 g, 0.74 mmol) in methylene chloride(7.43 mL). This solution was stirred at 25° C. for 1 h. At this time,the reaction was cooled to 0° C. and treated with a dilute aqueousammonium hydroxide solution. This mixture was stirred at 0° C. for 20min. At this time, the reaction was poured into water and was extractedwith chloroform (3×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethylacetate) afforded3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide (38.8mg, 15.7%) as a white solid: mp 170-173° C.; EI-HRMS m/e calcd forC₁₇H₂₀N₂O₃S (M⁺) 332.1194 found 332.1192.

EXAMPLE 1153-Cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide

[0603]

[0604] A solution of freshly prepared lithium diisopropylamide (58.5 mLof a 0.93M stock solution, 53.2 mmol) cooled to −78° C. was treated with(4-methoxy-phenyl)-acetic acid (4.21 g, 25.35 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Atthis time, the reaction was treated with a solution ofiodomethylcyclopentane (5.85 g, 27.8 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reactionmixture was stirred at −78° C. for 45 min and at 0° C. for 1 h. Thereaction was then warmed to 25° C. and was stirred at 25° C. for 16 h.The reaction mixture was then quenched by the dropwise addition ofsaturated aqueous ammonium chloride solution (10 mL). The excess solventwas removed in vacuo. The residue was acidified to pH=1 with a 1Naqueous hydrochloric acid solution. This mixture was poured into water(50 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with a saturated aqueous lithium chloride solution(1×100 mL), dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methoxy-phenyl)-propionic acid (2.76 g, 43.8%) as ayellow solid: mp 119-121° C.; EI-HRMS m/e calcd for C₁₅H₂₀O₃ (M⁺)248.1412 found 248.1415.

[0605] A solution of 3-cyclopentyl-2-(4-methoxy-phenyl)-propionic acid(500 mg, 2.0 mmol) in methylene chloride (20.1 mL) cooled to 0° C. wastreated with a 2.0M solution of oxalyl chloride in methylene chloride(1.1 mL, 2.21 mmol) and a few drops of N,N-dimethylformamide. Thereaction mixture was stirred at 0° C. for 10 min then at 25° C. for 30min. The reaction mixture was then treated with a solution of2-aminothiazole (444 mg, 4.42 mmol) and N,N-diisopropylethylamine (0.84mL, 4.83 mmol) in tetrahydrofuran (10.1 mL). This solution was stirredat 25° C. for 18 h. At this time, the reaction was concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide (638 mg,95.8%) as a pale yellow solid: mp 166-167° C.; EI-HRMS m/e calcd forC₁₈H₂₂N₂O₂S (M⁺) 330.1402 found 330.1398.

EXAMPLE 1163-Cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide

[0606]

[0607] A solution3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide (preparedas in Example 115, 1.03 g, 3.12 mmol) in methylene chloride (31.26 mL)at 25° C. was treated with a 1.0M solution of boron tribromide inmethylene chloride (31.26 mL, 31.26 mmol). This solution was stirred at25° C. for 4 h. At this time, the reaction was cooled to 0° C. and wasthen quenched by the dropwise addition of a dilute aqueous ammoniumhydroxide solution. The resulting solution was stirred at 0° C. for 15min. This mixture was then poured into water (50 mL) and extracted withethyl acetate (3×30 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethylacetate) afforded3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide (626.8mg, 63.4%) as a off-white solid: mp 198-200° C.; EI-HRMS m/e calcd forC₁₇H₂₀N₂O₂S (M⁺) 316.1245 found 316.1256.

EXAMPLE 117 4-[2-Cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoicacid methyl ester

[0608]

[0609] A solution of 4-methyl-benzoic acid (10 g, 73.4 mmol) in benzene(133 mL) was treated with benzoyl peroxide (72 mg, 0.29 mmol). Thismixture was heated at reflux until it became homogeneous. At this time,the reaction was treated with N-bromosuccinimide (13 g, 73.4 mmol) andadditional benzoyl peroxide (72 mg, 0.29 mmol). This mixture was heatedat reflux for 2.5 h. At this time, the reaction was cooled to 25° C. Theresulting precipitate was collected by filtration and washed with hotwater (50 mL). The solid was taken up in water (150 mL). This slurry washeated at 80° C. and then filtered while hot. The solid that wascollected was dried in vacuo to afford 4-bromomethyl-benzoic acid (12.3,77.9%) as a white solid: mp 224-226° C.; EI-HRMS m/e calcd for C₈H₇BrO₂(M⁺) 213.9629, found 213.9628.

[0610] A solution of 4-bromomethyl-benzoic acid (4.0 g, 18.6 mmol) inacetonitrile (186 mL) was treated with a solution of sodium cyanide (1.0g, 20.4 mmol) and sodium hydroxide (0.74 g, 18.6 mmol) in water (24 mL).The reaction mixture was heated at reflux for 2 h. At this time, thereaction was cooled to 25° C. and concentrated in vacuo. The resultingsolution was washed with chloroform (1×50 mL). The aqueous layer wasacidified to pH=3 with a 1N aqueous hydrochloric acid solution. Theaqueous layer was extracted with a solution of chloroform/methanol (9:1,3×100 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo to afford 4-cyanomethyl-benzoic acid(0.79 g, 26.3%) as a white solid: mp 193-195° C.; EI-HRMS m/e calcd forC₉H₇NO₂ (M⁺) 161.0476, found 161.0483.

[0611] A solution of 4-cyanomethyl-benzoic acid (0.53 g, 3.31 mmol) in a50% aqueous hydrochloric acid solution (42.8 mL) was heated at 80° C.for 16 h. At this time, the reaction was cooled to 25° C. and adjustedto pH=3 by the dropwise addition of a 50% aqueous sodium hydroxidesolution. The resulting mixture was diluted with water and extractedwith butanol (2×50 mL). The combined organic layers were then extractedwith water (5×50 mL, pH=6-7). The aqueous extracts were adjusted to pH=3with a 3M aqueous hydrochloric acid solution and concentrated in vacuoto afford 4-carboxymethyl-benzoic acid (70 mg, 11.7%) as a white solid:mp 235-237° C.; EI-HRMS m/e calcd for C₉H₈O₄ (M⁺) 180.0422, found 180.

[0612] A mixture of 4-carboxymethyl-benzoic acid (0.20 g, 1.11 mmol) andnickel(II) chloride hexahydrate (27 mg, 0.11 mol) in methanol (1.11 mL)was heated at 120° C. for 24 h. At this time, the reaction mixture wascooled to 25° C. and concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded4-methoxycarbonylmethyl-benzoic acid methyl ester (66.7 mg, 28.8%) as aclear oil: EI-HRMS m/e calcd for C₁₁H₁₂O₄(M⁺) 208.0735, found 208.0733.

[0613] A solution of freshly prepared lithium diisopropylamide (2.3 mLof a 0.31 M stock solution, 0.71 mmol) cooled to −78° C. was treatedwith a solution of 4-methoxycarbonylmethyl-benzoic acid methyl ester (66mg, 0.31 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.85mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Atthis time, the reaction was treated with a solution ofiodomethylcyclopentane (86 mg, 0.40 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reactionmixture was then stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and stirred at 25° C. for 18 h. At this time, thereaction mixture was quenched by the slow addition of a saturatedaqueous ammonium chloride solution (10 mL). The reaction mixture wasthen poured into water (50 mL). This solution was extracted into ethylacetate (3×25 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)afforded 4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoic acid methylester (60.5 mg, 65.7%) as a clear oil: EI-HRMS m/e calcd for C₁₇H₂₂O₄(M⁺) 290.1518, found 290.1518.

[0614] A solution of 4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoicacid methyl ester (0.40 g, 1.37 mmol) in tetrahydrofuran/water/methanol(13.7 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxidesolution. The reaction mixture was stirred at 25° C. for 1 h. At thistime, the reaction was poured into water. The aqueous layer wasacidified to pH=1 with a 1N aqueous hydrochloric acid solution andextracted with a solution of chloroform/methanol (9:1, 4×25 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded a mixture of4-(1-carboxy-2-cyclopentyl-ethyl)-benzoic acid methyl ester and4-(1-carboxy-2-cyclopentyl-ethyl)-benzoic acid methyl ester (161.8 mg,42.5%) as a clear oil: EI-HRMS m/e calcd for C₁₆H₂₀O₄(M⁺) 276.1361,found 276.1364.

[0615] A solution of the mixture of4-(1-carboxy-2-cyclopentyl-ethyl)-benzoic acid methyl ester and4-(1-carboxy-2-cyclopentyl-ethyl)-benzoic acid methyl ester (24.2 mg,0.08 mmol) in methylene chloride (0.87 mL) cooled to 0° C. was treatedwith a 2.0M solution of oxalyl chloride in methylene chloride (0.05 mL,0.10 mmol) and a few drops of N,N-dimethylformamide. The reactionmixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. Thereaction mixture was then treated with a solution of 2-aminothiazole(19.3 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.21 mmol)in tetrahydrofuran (0.44 mL). The reaction mixture was stirred at 25° C.for 4 h. At this time, the reaction was concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethylacetate) afforded4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid methylester (18.1 mg, 57.6%) as an off-white solid: mp 54-56° C.; EI-HRMS m/ecalcd for C₁₉H₂₂N₂O₃S (M⁺) 358.1351, found 358.1346.

EXAMPLE 1183-Cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide

[0616]

[0617] A solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.0 g,5.87 mmol) in methanol (20 mL) was treated with a catalytic amount ofsulfuric acid. The reaction was heated at 120° C. for 6 h. At this time,the reaction was concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded(3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (1.05 g, 97.6%) asa white solid: mp 34-36° C.: EI-HRMS m/e calcd for C₉H₉FO₃ (M⁺)184.0535, found 184.0533.

[0618] A mixture of 3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester(1.0 g, 5.43 mmol), potassium carbonate (1.87 g, 13.57 mmol), and methyliodide (1.12 g, 8.14 mmol) in acetone (27.1 mL) was heated at 90° C. for4 h. At this time, the potassium carbonate was removed by filtration.The filtrate was concentrated in vacuo. Flash chromatography (MerckSilica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded(3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.01 g, 94.3%) asa clear oil: EI-HRMS m/e calcd for C₁₀H₁₁FO₃(M⁺) 198.0692, found198.0693.

[0619] A solution of freshly prepared lithium diisopropylamide (21.6 mLof 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with asolution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26g, 6.38 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Atthis time, the reaction was treated with a solution ofiodomethylcyclopentane (1.47 g, 7.02 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reactionmixture was stirred at −78° C. for 4 h. The reaction was warmed to 25°C. and stirred at 25° C. for 48 h. The reaction mixture was thenquenched by the slow addition of a saturated aqueous ammonium chloridesolution (10 mL). The reaction mixture was then poured into water (100mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with a saturated aqueous lithium chloride solution(1×50 mL), dried over sodium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester(1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C₁₆H₂₁FO₃(M⁺)280.1477 found 280.1474.

[0620] A solution of3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester(1.04 g, 3.73 mmol) in tetrahydrofuran/water/methanol (9.3 mL, 3:1:1)was treated with a 1N aqueous lithium hydroxide solution (3.73 mL, 3.73mmol). The reaction was stirred at 25° C. for 18 h. At this time, thereaction was acidified to pH=1 with a 1N aqueous hydrochloric acidsolution and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 50/50 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid (707.8 mg,71.3%) as a white solid: mp 149-151° C.; EI-HRMS m/e calcd for C₁₅H₁₉FO₃(M⁺) 266.1318 found 266.1317.

[0621] A solution of3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid (400.0 mg,1.50 mmol) in methylene chloride (5.0 mL) cooled to 0° C. was treatedwith a 2.0M solution of oxalyl chloride in methylene chloride (0.82 mL,1.65 mmol) and a few drops of N,N-dimethylformamide. The reactionmixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. Thereaction mixture was then treated with a solution of 2-aminothiazole(331 mg, 3.30 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.60 mmol)in tetrahydrofuran (7.5 mL). This solution was stirred at 25° C. for 18h. At this time, the reaction was concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethylacetate) afforded3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide(538.4 mg, 100%) as a white solid: mp 51-53° C.: EI-HRMS m/e calcd forC₁₈H₂₁FN₂O₂S (M⁺) 348.1307 found 348.1312.

EXAMPLE 1193-Cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide

[0622]

[0623] A solution of3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide(prepared as in Example 118, 305.4 mg, 0.87 mmol) in methylene chloride(8.7 mL) at 25° C. was treated with a 1.0M solution of boron tribromidein methylene chloride (8.75 mL, 8.75 mmol). This solution was stirred at25° C. for 5 h. At this time, the reaction was cooled to 0° C. andquenched by the dropwise addition of a dilute aqueous ammonium hydroxidesolution. The resulting solution was stirred at 0° C. for 15 min. Thismixture was then poured into water (50 mL) and extracted with ethylacetate (3×30 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate)afforded3-cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide(212.7 mg, 72.5%) as a white solid: mp 199-201° C.: EI-HRMS m/e calcdfor C₁₇H₁₉FN₂O₂S (M⁺) 334.1151 found 334.1152.

EXAMPLE 1206-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid

[0624]

[0625] A solution of freshly prepared lithium diisopropylamide (141.3 mLof a 0.32M stock solution, 45.0 mmol) cooled to −78° C. was treated with(3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) intetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. At thistime, the reaction was treated with a solution of iodomethylcyclopentane(4.64 g, 22.08 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). Thereaction mixture was stirred at −78° C. for 4 h. The reaction was thenwarmed to 25° C. and was stirred at 25° C. for 48 h. This solution wasthen quenched by the slow addition of the reaction mixture to a 2Naqueous hydrochloric acid solution (50 mL). The product was extractedinto ethyl acetate (1×150 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate)afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g,72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd forC₁₄H₁₇ClO₂(M⁺) 252.0917, found 252.0915.

[0626] A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid(504 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to 0° C. wastreated with a 2.0M solution of oxalyl chloride in methylene chloride(1.1 mL, 2.2 mmol) and a few drops of N,N-dimethylformamide. Thereaction mixture was stirred at 0° C. for 15 min and at 25° C. for 2 h.The reaction mixture was then treated with 6-amino-nicotinic acid methylester (532 mg, 3.5 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.8mmol). This solution was stirred at 25° C. for 18 h. At this time, thereaction was concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester (151.9 mg, 19.7%) as a colorless oil: EI-HRMS m/e calcd forC₂₁H₂₃ClN₂O₃ (M⁺) 386.1397, found 386.1398.

[0627] A solution of6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester (146.9 mg, 0.38 mmol) in tetrahydrofuran/water/methanol (10mL, 3:1:1) at 25° C. was treated with a 2N aqueous sodium hydroxidesolution (0.4 mL, 0.80 mmol). The reaction mixture was stirred at 25° C.for 4 d. At this time, the reaction was concentrated in vacuo. Theresidue was diluted with water (50 mL) and extracted with diethyl ether(1×50 mL). The aqueous layer was acidified to pH=1 by the dropwiseaddition of a 3N aqueous hydrochloric acid solution. This solution wasextracted with a solution of methylene chloride/methanol (3:1, 3×75 mL).The combined organic layers were dried over magnesium sulfate, filtered,and concentrated in vacuo. The resulting solid was triturated withdiethyl ether/hexanes (2:1) to afford6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid(63.6 mg, 44.4%) as a white solid: mp 251-255° C.; EI-HRMS m/e calcd forC₂₀H₂₁ClN₂O₃ (M⁺) 372.1240, found 372.1250.

EXAMPLE 1216-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acidmethyl ester

[0628]

[0629] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid(prepared as in Example 22A, 526 mg, 2.0 mmol) in methylene chloride (20mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloridein methylene chloride (1.2 mL, 2.4 mmol) and a few drops ofN,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15min and at 25° C. for 30 min. The reaction mixture was then treated witha solution of 6-amino-nicotinic acid methyl ester (532 mg, 3.5 mmol) intetrahydrofuran (10 mL) and N,N-diisopropylethylamine (0.84 mL, 4.8mmol). This solution was stirred at 25° C. for 48 h. At this time, thereaction was concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acidmethyl ester (353.9 mg, 44.6%) as a pale orange glass: EI-HRMS m/e calcdfor C₂₁H₂₃N₃O₅(M⁺) 397.1637, found 397.1631.

EXAMPLE 122 2-(4-Amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide

[0630]

[0631] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid(prepared as in Example 22A, 263 mg, 1.0 mmol) in methylene chloride (10mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloridein methylene chloride (0.6 mL, 1.2 mmol) and a few drops ofN,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15min and at 25° C. for 30 min. The reaction mixture was then treated witha solution of 2-aminopyridine (200.6 mg, 2.14 mmol) in tetrahydrofuran(5 mL) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). This solutionwas stirred at 25° C. for 48 h. At this time, the reaction wasconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 80/20 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (138.6 mg,40.9%) as a pale yellow glass: EI-HRMS m/e calcd for C₁₉H₂₁N₃O₃(M⁺)339.1581, found 339.1582.

[0632] A mixture of3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (130 mg,0.38 mmol) in ethyl acetate (50 mL) and methanol (5 mL) was treated witha catalytic amount of 10% palladium on activated carbon (50 mg). Theresulting mixture was shaken at 25° C. under 60 psi of hydrogen gas in aParr apparatus for 24 h. At this time, the catalyst was removed byfiltration through a plug of celite. The filtrate was concentrated invacuo to afford2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (99.9 mg,84.3%) as a tan oil: EI-HRMS m/e calcd for C₁₉H₂₃N₃O (M⁺) 309.1834,found 309.1849.

EXAMPLE 1236-[2-(4-Amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester

[0633]

[0634] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid(prepared as in Example 22A, 526 mg, 2.0 mmol) in methylene chloride (20mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloridein methylene chloride (1.2 mL, 2.4 mmol) and a few drops ofN,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15min and at 25° C. for 30 min. The reaction mixture was then treated witha solution of 6-amino-nicotinic acid methyl ester (532 mg, 3.5 mmol) intetrahydrofuran (10 mL) and N,N-diisopropylethylamine (0.84 mL, 4.8mmol). This solution was stirred at 25° C. for 48 h. At this time, thereaction was concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acidmethyl ester (353.9 mg, 44.6%) as a pale orange glass: EI-HRMS m/e calcdfor C₂₁H₂₃N₃O₅(M⁺) 397.1637, found 397.1631.

[0635] A mixture of6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acidmethyl ester (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was treatedwith a catalytic amount of 10% palladium on activated carbon (30 mg).The resulting mixture was shaken at 25° C. under 60 psi of hydrogen gasin a Parr apparatus for 24 h. At this time, the catalyst was removed byfiltration through a plug of celite. The filtrate was concentrated invacuo to afford6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester (262.8 mg, 94.7%) as a pale yellow glass: EI-HRMS m/e calcdfor C₂₁H₂₅N₃O₃ (M⁺) 367.1895, found 367.1899.

EXAMPLE 1243-Cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide

[0636]

[0637] A solution of isoamyl nitrite (4.02 mL, 30 mmol) in dimethyldisulfide (19.8 mL, 220 mmol) at 25° C. was slowly treated with4-bromo-2-(trifluoromethyl)aniline (4.8 g, 20 mmol). The reaction wasexothermic with gas evolution. The resulting brown reaction mixture washeated to 80-90° C. for 2 h, at which time, thin layer chromatographyanalysis of the reaction mixture indicated the absence of startingmaterial. The reaction mixture was cooled to 25° C. and thenconcentrated in vacuo. The resulting residue was dissolved in ethylacetate (200 mL). The organic layer was washed successively with a 1Naqueous hydrochloric acid solution (1×200 mL) and a saturated aqueoussodium chloride solution (1×200 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (4.73 g, 87%) as abrown oil: EI-HRMS m/e calcd for C₈H₆BrF₃S (M⁺) 269.9326, found269.9327.

[0638] A solution of 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene(4.71 g, 17.4 mmol) in methylene chloride (100 mL) was cooled to -10° C.and then treated with 3-chloroperoxybenzoic acid (86% grade, 9.0 g, 52.2mmol). The reaction mixture was stirred at −10° C. for 10 min and thenallowed to warm to 25° C. where it was stirred overnight. At this time,thin layer chromatography analysis of the reaction mixture indicated theabsence of starting material. The reaction mixture was then filtered,and the solids were washed with methylene chloride (1×50 mL). Thefiltrate was concentrated in vacuo. The resulting residue was dissolvedin ethyl acetate (100 mL). The organic layer was washed successivelywith a saturated aqueous sodium bicarbonate solution (2×100 mL) and asaturated aqueous sodium chloride solution (1×100 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford a yellow solid. Recrystallization from methylene chloride (20mL), diethyl ether (10 mL), and hexanes afforded4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene (3.46 g, 57%) as awhite solid: mp 110-112 ° C.; EI-HRMS m/e calcd for C₈H₆BrF₃O₂S (M⁺)301.9224, found 301.9223.

[0639] A mixture of zinc dust (1.3 g, 20 mmol, Aldrich, -325 mesh) anddry tetrahydrofiran (2 mL) under argon was treated with1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heatedwith a heat gun to ebullition, allowed to cool, and heated again. Thisprocess was repeated three times to make sure the zinc dust wasactivated. The activated zinc dust suspension was then treated withtrimethylsilyl chloride (110 mg, 1 mmol), and the suspension was stirredfor 15 min at 25° C. The reaction mixture was then treated dropwise witha solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester(prepared as in Example 108, 2.5 g, 8.5 mmol) in dry tetrahydrofuran (3mL) over 5 min. After the addition, the reaction mixture was stirred for1 h at 40-45° C. and then stirred overnight at 25° C. The reactionmixture was then diluted with dry tetrahydrofuran (4 mL), and thestirring was stopped to allow the excess zinc dust to settle down (˜2h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)(108 mg, 0.2 mmol) and triphenylphosphine (209 mg, 0.8 mmol) in drytetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min andthen treated with 4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene(2.12 g, 7 mmol) and the freshly prepared zinc compound intetrahydroftiran. The resulting brick red solution was heated at 40-45°C. for 2 d. The reaction mixture was cooled to 25° C. and then pouredinto a saturated aqueous ammonium chloride solution (100 mL), and theorganic compound was extracted into ethyl acetate (3×75 mL). Thecombined organic extracts were washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M,Silica, 9/1 to 3/1 hexanes/ethyl acetate) afforded(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylicacid methyl ester (2.7 g, 99%) as a viscous oil: EI-HRMS m/e calcd forC₁₈H₂₁F₃O₄S (M⁺) 391.1191, found 391.1200.

[0640] A solution of nickel(II) chloride hexahydrate (36.6 mg, 0.154mmol) and(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylicacid methyl ester (302 mg, 0.77 mmol) in methanol (8 mL) was cooled to0° C. and then treated with sodium borohydride (87 mg, 2.29 mmol) infour portions. After the addition, the black reaction mixture wasstirred for 15 min at 0° C. and then allowed to warm to 25° C. where itwas stirred for 15 h. The black solid was filtered using filter paperand washed with methanol. The combined solvents were concentrated invacuo, and the residue was diluted with ethyl acetate (50 mL). Theorganic layer was washed successively with a 3N aqueous hydrochloricacid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution(1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo to afford racemic3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (280 mg, 93%) as a viscous oil: EI-HRMS m/e calcd forC₁₈H₂₃F₃O₄S (M⁺) 392.1269, found 392.1276.

[0641] A solution of3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (265 mg, 0.67 mmol) in ethanol (5 mL) was treated witha 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heatedat 45-50° C. for 5 h, at which time, thin layer chromatography analysisof the mixture indicated the absence of starting material. The reactionmixture was then concentrated in vacuo to remove ethanol, and theresidue was diluted with water (20 mL) and extracted with diethyl ether(1×40 mL) to remove any neutral impurities. The aqueous layer wasacidified with a 1N aqueous hydrochloric acid solution. The resultingacid was extracted into ethyl acetate (2×50 mL). The combined organiclayers were washed with a saturated aqueous sodium chloride solution(1×50 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (249 mg, 97%) as a viscous oil: EI-HRMS m/e calcd for C₁₇H₂₁F₃O₄S(M⁺) 378.1113, found 378.1121.

[0642] A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylenechloride (5 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (188.7 mg, 1.06 mmol). The reaction mixture wasstirred at 0° C. for 30 min and then treated with a solution of3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (237 mg, 0.626 mmol) in methylene chloride (4 mL). The clearsolution was stirred for 15 min at 0° C. and then allowed to warm to 25°C. where it was stirred for 2 h. The reaction mixture was then treatedwith 2-aminothiazole (188 mg, 1.88 mmol), and the resulting suspensionwas stirred for 15 h at 25° C. The reaction mixture was concentrated invacuo to remove methylene chloride, and the residue was diluted withethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50mL). The two layers were separated, and the aqueous layer was extractedwith ethyl acetate (1×30 mL). The combined organic extracts weresuccessively washed with a saturated aqueous sodium bicarbonate solution(1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1hexanes/ethyl acetate) afforded3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide(83 mg, 29%) as an amorphous solid: EI-HRMS m/e calcd for C₂₀H₂₃F₃N₂O₃S₂(M⁺) 460.1102, found 460.1100.

EXAMPLE 1253-Cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0643]

[0644] A solution of (4-mercapto-phenyl)-acetic acid (1.00 g, 5.94 mmol)in methanol (10 mL) was treated with a catalytic amount of concentratedsulfuric acid (2 drops). The reaction was heated under reflux for 2 h.At this time, the reaction mixture was concentrated in vacuo. Theresidue was re-dissolved in chloroform and washed with a saturatedaqueous sodium bicarbonate solution. The organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford(4-mercapto-phenyl)-acetic acid methyl ester (1.04 g, 96%) as acolorless oil: EI-HRMS m/e calcd for C₉H₁₀O₂S (M⁺) 182.0402, found182.0405.

[0645] A solution of (4-mercapto-phenyl)-acetic acid methyl ester (500mg, 2.7 mmol) and chloromethyl methyl ether (331 mg, 4.1 mmol) inacetonitrile (3 mL) and pyridine (1 mL) was heated under reflux for 16h. At this time, the reaction was concentrated in vacuo. The residue wasre-dissolved in ethyl acetate (10 mL) and was washed with a 1N aqueoushydrochloric acid solution (2×25 mL) and a saturated aqueous sodiumchloride solution. The organic layer was dried over magnesium sulfate,filtered and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded(4-methoxymethylsulfanyl-phenyl)-acetic acid methyl ester (482 mg,77.6%) as a clear oil: EI-HRMS m/e calcd for C₁₁H₁₄O₃S (M⁺) 226.0664,found 226.0664.

[0646] A solution of (4-methoxymethylsulfanyl-phenyl)-acetic acid methylester (441 mg, 1.90 mmol) in methanol (1 mL), water (0.5 mL), andtetrahydrofuran (0.5 mL) was treated with lithium hydroxide (51 mg, 2.1mmol). The reaction mixture was stirred at 25° C. for 20 h. At thistime, the reaction was concentrated in vacuo. The residue wasre-dissolved in water and extracted with ethyl acetate. The aqueouslayer was then acidified to pH=1 with a 1N aqueous hydrochloric acidsolution. This solution was extracted with ethyl acetate. The combinedorganic extracts were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford (4-methoxymethylsulfanyl-phenyl)-aceticacid (402 mg, 100%) as a clear oil which was used without furtherpurification.

[0647] A solution of diisopropylamine (0.37 mL, 2.62 mmol) intetrahydrofuran (2 mL) was cooled to −78° C. and then treated with a2.5M solution of n-butyllithium in hexanes (1.05 mL, 2.62 mmol). Thissolution was stirred at −78° C. for 30 min and then treated with asolution of (4-methoxymethylsulfanyl-phenyl)-acetic acid (223 mg, 1.05mmol) in tetrahydrofuran (1.5 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL). Thereaction mixture was allowed to stir at −78° C. for 1 h. At this time,the reaction was treated with iodomethylcyclopentane (328 mg, 1.56mmol). The reaction mixture was allowed to slowly warm to 25° C. whereit was stirred for 18 h. At this time, the reaction mixture was quenchedwith a saturated aqueous sodium bicarbonate solution and thenconcentrated in vacuo. The residue was treated with a 1N aqueous sodiumhydroxide solution and extracted with ethyl acetate. The aqueous layerwas then acidified with concentrated hydrochloric acid. This solutionwas extracted with ethyl acetate. The combined organic extracts weredried over magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 12M, Silica, 80/20 hexanes/ethyl acetate)afforded 3-cyclopentyl-2-(4-methoxymethylsulfanyl-phenyl)-propionic acid(202 mg, 65%) as an off-white solid: mp 167-170° C.; EI-HRMS m/e calcdfor C₁₆H₂₂O₃S (M⁺) 294.1290, found 294.1288.

[0648] A solution of3-cyclopentyl-2-(4-methoxymethylsulfanyl-phenyl)-propionic acid (50 mg,0.17 mmol) in methanol (1 mL), water (0.2 mL), and pH=4 phosphate buffer(0.5 mL) at 25° C. was treated with oxone (314 mg, 0.51 mmol). Thereaction was stirred at 25° C. for 6 h. At this time, the reaction wasconcentrated in vacuo. The residue was dissolved in ethyl acetate andwashed with a 1N aqueous hydrochloric acid solution (2×25 mL). Theorganic layer was then dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford3-cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-propionic acid (35 mg,63.2%) as a white solid: mp 184-187° C.; EI-HRMS m/e calcd for C₁₆H₂₂O₅S(M⁺) 326.1188, found 326.1189.

[0649] A solution of3-cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-propionic acid (31 mg,0.09 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (67 mg, 0.15 mmol), and 2-aminothiazole (15 mg, 0.15mmol) in methylene chloride (1 mL) at 25° C. was treated withtriethylamine (0.04 mL, 0.29 mmol). The reaction was stirred at 25° C.for 20 h. At this time, the reaction was treated with a saturatedaqueous sodium bicarbonate solution. The resulting organic layer waswashed with a 1N aqueous hydrochloric acid solution, dried overmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethylacetate) afforded3-cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(23 mg, 59.2%) as a white solid: mp 157-160° C.; EI-HRMS m/e calcd forC₁₉H₂₄N₂O₄S₂ (M⁺) 408.1178, found 408.1178.

EXAMPLE 1263-Cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-propionamide

[0650]

[0651] A mixture of 4-(methylthio)phenylacetic acid (50 g, 272 mmol) intetrahydrofuran (250 mL) was treated with freshly powdered potassiumcarbonate (93.8 g, 679 mmol). A very mild exotherm ensued, and theresulting white suspension was stirred at 25-26° C. for 30 min. Thereaction mixture was then cooled to −10° C. and treated withtrimethylacetyl chloride (35.5 mL, 285 mmol) over 30 min. Aftercompletion of the addition, the reaction mixture was then stirred at−10° C. to −5° C. for 30 min and then treated with(1R,2R)-(−)-pseudoephedrine (59.5 g, 353 mmol) in portions over 15 minwhile maintaining the temperature of the reaction mixture between −10°C. and −4° C. The reaction mixture was then stirred at −7° C. to 0° C.for 3 h. The reaction mixture was then quenched at 0° C. by the additionof water (150 mL). After vigorously stirring for 10 min, toluene (150mL) was added, and the reaction mixture was stirred for 5 min. Theorganic layer was separated and washed with water (2×100 mL). Thecombined aqueous layers were back-extracted with toluene (1×50 mL). Thecombined organic layers were washed with 1N aqueous sulfuric acidsolution (1×200 mL), a saturated aqueous sodium bicarbonate solution(1×200 mL), and a solution of water/saturated aqueous sodium chloridesolution (1:1, 1×50 mL). The resulting organic layer was thenconcentrated in vacuo to afford a white solid. This white solid wasdried overnight under high vacuum (0.4 mm Hg) to afford crudeN-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2-(4-methylsulfanyl-phenyl)-acetamide(82.8 g, 92.6% pure by HPLC analysis). This material was dissolved intoluene (225 mL) at reflux. After standing in a refrigerator over theweekend, the resulting crystalline material was collected by filtration,washed with cold toluene (3×35 mL), and dried under high vacuum toaffordN-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2-(4-methylsulfanyl-phenyl)-acetamide(66.1 g, 73.1%) as white crystals: mp 112-113° C.; 99.6% pure by HPLCanalysis. HPLC conditions as follows: Column: ES Si, 3μ, 5 × 150 mmMobile Phase: 30% THF in heptane at 1 mL/min Detection: UV, 259 nmRetention Time: 20 min

[0652] A solution of triphenylphosphine (28.80 g, 109.8 mmol) andimidazole (14.9 g, 219.6 mmol) in methylene chloride (160 mL) was cooledto 0° C. and then slowly treated with iodine (27.87 g, 109.8 mmol). Thereaction mixture was then treated dropwise with a solution ofcyclopentylmethanol (10.00 g, 99.8 mmol) in methylene chloride (10 mL).The resulting reaction mixture was allowed to warm to 25° C. where itwas stirred for for 4 h. The reaction mixture was then diluted withwater (50 mL), and the reaction mixture was further extracted withmethylene chloride (3×20 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo at 25° C. Theresulting solid was washed with pentane (4×50 mL) and filtered through asilica gel plug. The filtrate was concentrated in vacuo at 25° C. toafford iodomethylcyclopentane (18.48 g, 88%) as a clear colorlessliquid: EI-HRMS m/e calcd for C₆H₁₁I (M⁺) 209.9906, found 209.9911.

[0653] A solution of 1,1,1,3,3,3-hexamethyldisilazane (98.4 mL, 457mmol) in tetrahydrofuran (400 mL) was cooled to −20° C. and then treatedwith a 2.29M solution of n-butyllithium in hexanes (182 mL, 418 mmol)over 35 min while maintaining the temperature between −20° C. and −15°C. The reaction mixture was stirred at −20° C. for 30 min and then wastreated with a solution of N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2-(4-methylsulfanyl-phenyl)-acetamide(66.1 g, 201 mmol) in tetrahydrofuran (500 mL) over 50 min whilemaintaining the temperature between −20° C. and −15° C. The resultingyellow solution was stirred at 0° C. for 30 min and then treated with apremixed solution of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone(51 mL, 418 mmol) and iodomethylcyclopentane (50.6 g, 239 mmol) over 30min. The resulting reaction mixture was stirred at 0° C. for 4 h, atwhich time, thin layer chromatography analysis indicated that thereaction was complete. The reaction mixture was then poured into toluene(400 mL). The organic phase was washed sequentially with a solution ofwater/saturated aqueous sodium chloride solution (1:1, 1×1000 mL), asolution of water/saturated aqueous sodium chloride solution (1:2,1×1000 mL), a 1M aqueous sulfuric acid solution (1×800 mL), water (1×200mL), and a saturated aqueous sodium bicarbonate solution (1×1000 mL).The resulting organic layer was concentrated in vacuo to afford crude3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2(R)-(4-methylsulfanyl-phenyl)-propionamideas an oily yellow residue (98.5% de by HPLC analysis). This material wasdissolved in ethyl acetate (70 mL) and subsequently treated with hexanes(200 mL). The solution was stored in a freezer over the weekend. Theresulting solid was collected by filtration, washed with cold hexanes(ca. −10° C., 3×30 mL), and then dried under high vacuum to afford3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2(R)-(4-methylsulfanyl-phenyl)-propionamide(48.8 g, 59%) as a white solid: mp 82-84° C.; 100% de by HPLC analysis.The combined filtrate and washes were concentrated in vacuo, and theresidue (34.4 g) was placed on top of a plug of thin layerchromatography grade silica gel (2-25 μl, 70 g). The silica gel plug wasthen washed with a solution of hexanes/ethyl acetate (4:1, 1.5 L), andthe combined eluates were concentrated in vacuo. The resultingpale-yellow oil was dissolved in ethyl acetate (35 mL) and subsequentlytreated with hexanes (100 mL). The solution was stored in a refrigeratorovernight. The resulting solid was collected by filtration, washed withcold hexanes (ca. −10° C., 3×25 mL), and dried under high vacuum toafford3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2(R)-(4-methylsulfanyl-phenyl)-propionamide(17.3 g, 20.9%) as a white solid: mp 83-85° C.; 99.6% de by HPLCanalysis. These two crops were combined to afford the desireddiastereomer, 3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2(R)-(4-methylsulfanyl-phenyl)-propionamide(66.1 g, 79.9%), as a white solid. HPLC conditions as follows: Column:ES Si, 3μ, 5 × 150 mm Mobile Phase: 20% THF in heptane at 1 mL/minDetection: UV, 259 nm Retention Time: 9.2 min (undesired diastereomer)and 14.4 min (desired diastereomer)

[0654] A solution of3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2(R)-(4-methylsulfanyl-phenyl)-propionamide(4.00 g, 9.72 mmol) in dioxane (8 mL) was treated with a 9N aqueoussulfuric acid solution (7.7 mL). The two-phase mixture was heated atreflux, resulting in a homogeneous colorless solution. After heating atreflux for 16 h, the reaction mixture was cooled to 5° C. with anice-water bath and then treated dropwise with water (20 mL) toprecipitate the product. After the resulting suspension was stirred for1 h with ice-water cooling, the solid was collected by filtration,washed with water (4×10 mL), and dried by suction to afford crude3-cyclopentyl-2R-(4-methylsulfanyl-phenyl)-propionic (2.57 g, 96.6%,96.3% ee by chiral HPLC analysis) as a light tan solid. This materialwas dissolved in glacial acetic acid (5 mL) at reflux and then treatedwith water (1 mL) to initiate crystallization. The heating bath wasremoved, and then water (4 mL) was added dropwise to the suspension tocomplete the crystallization. The mixture was allowed to cool to ambienttemperature. After stirring for 1 h, the solid was collected byfiltration. The solid was washed with a solution of acetic acid/water(1:1, 10 mL) and water (4×10 mL), and then dried to afford3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-propionic (2.24 g, 87.2%)as a white solid: mp 75-76° C.; 96.4% ee by chiral HPLC analysis. ChiralHPLC conditions as follows: Column: Chiralpak AS, 5μ, 5 × 250 mm MobilePhase: 6% isopropanol in hexane + 0.1% TFA at 0.5 mL/min Detection: UV,259 nm Retention Time: 13.2 min (desired R-isomer) and 17.1 min(S-isomer)

[0655] A solution of3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-propionic acid (529 mg, 2.0mmol) and triphenylphosphine (892 mg, 3.4 mmol) in methylene chloride(10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide(605 mg, 3.4 mmol) in small portions. The reaction mixture color changedfrom light yellow to a darker yellow then to brown. After the completeaddition of the N-bromosuccinimide, the reaction mixture was allowed towarm to 25° C. over 30 min. The brown reaction mixture was then treatedwith 2-aminopyrazine (476 mg, 5.0 mmol). The resulting reaction mixturewas stirred at 25° C. for 19 h. The reaction mixture was thenconcentrated in vacuo to remove methylene chloride. The remaining blackresidue was diluted with a 10% aqueous hydrochloric acid solution (40mL) and then extracted with ethyl acetate (3×25 mL). The combinedorganic layers were washed with a saturated aqueous sodium chloridesolution (1×20 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 65/35hexanes/ethyl acetate) afforded3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-propionamide(102 mg, 15%) as a white solid: mp 128-130° C., [α]²³ ₅₈₉=−103.1°(c=0.032, chloroform); EI-HRMS m/e calcd for C₁₉H₂₃N₃OS (M⁺) 341.1562,found 341.1563.

EXAMPLE 1273-Cyclopentyl-2(R)-(4-methylsulfonyl-phenyl)-N-pyrazin-2-yl-propionamide

[0656]

[0657] A solution of3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-propionamide(prepared as in Example 126, 68 mg, 0.20 mmol) in formic acid (0.24 mL)was cooled to 0° C. and then treated with a 30% aqueous hydrogenperoxide solution (0.11 mL, 1.0 mmol). The resulting solution wasstirred at 0° C. for 3 h. The reaction was then concentrated in vacuo.Biotage chromatography (FLASH 12M, Silica, 1/1 hexanes/ethyl acetate)afforded3-cyclopentyl-2(R)-(4-methylsulfonyl-phenyl)-N-pyrazin-2-yl-propionamide(58 mg, 77%) as a white foam: mp 75-80° C., [α]²³ ₅₈₉=−29.4° (c=0.034,chloroform); EI-HRMS m/e calcd for C₁₉H₂₃N₃O₃S(M⁺) 373.1460, found373.1451.

EXAMPLE 1283-Cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(4-methyl-thiazol-2-yl)-propionamide

[0658]

[0659] A solution of3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-propionic (prepared as inExample 126, 50.03 g, 189.21 mmol) in formic acid (189 mL) was cooled to0° C. and then slowly treated with a 30% aqueous hydrogen peroxidesolution (58 mL, 567.64 mmol). The resulting reaction mixture wasallowed to stir at 0° C. for 1 h and then allowed to warm to 25° C.where it was stirred for 3 h. The reaction mixture was re-cooled to 0°C. and then slowly quenched with a saturated aqueous sodium bisulfitesolution (500 mL). A precipitate formed. The resulting suspension wasstirred at 0° C. for 1 h and then the solid was filtered. The solid waswashed with cold water (4×700 mL) and dried by suction to afford3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid as a creamsolid: mp 138-140° C.; [α]²³ ₅₈₉=−50.0° (c=0.02, chloroform); EI-HRMSm/e calcd for C₁₅H₂₀O₄S (M⁺) 296.1082, found 296.1080.

[0660] A solution of triphenylphosphine (345 mg, 1.31 mmol) in methylenechloride (4 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (234 mg, 1.31 mmol). The reaction mixture was stirredat 0° C. for 15 min and then treated with3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (300 mg, 1.01mmol). The resulting reaction mixture was stirred at 0° C. for 5 min andthen allowed to warm to 25° C. where it was stirred for 25 min. Thereaction mixture was then treated with 2-amino-4-methylthiazole (288 mg,2.52 mmol). The resulting reaction mixture was allowed to stir at 25° C.for 20 h. The reaction mixture was then diluted with water (30 mL), a 1Naqueous hydrochloric acid solution (5 mL), and ethyl acetate (30 mL).The layers were separated, and the organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(4-methyl-thiazol-2-yl)-propionamide(192 mg, 48%) as an off-white foam: mp 83-87° C. (foam to gel); [α]²³₅₈₉=−35.70 (c=1.01, chloroform); EI-HRMS m/e calcd for C₁₉H₂₄N₂O₃S₂ (M⁺)392.1228, found 392.1227.

EXAMPLE 1293-Cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methyl-thiazol-2-yl)-propionamide

[0661]

[0662] A solution of triphenylphosphine (345 mg, 1.31 mmol) in methylenechloride (4 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (234 mg, 1.31 mmol). The reaction mixture was stirredat 0° C. for 15 min and then treated with3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared asin Example 128, 300 mg, 1.01 mmol). The resulting reaction mixture wasstirred at 0° C. for 5 min and then allowed to warm to 25° C. where itwas stirred for 25 min. The reaction mixture was then treated with2-amino-5-methylthiazole (288 mg, 2.52 mmol). The resulting reactionmixture was allowed to stir at 25° C. for 20 h. The reaction mixture wasthen diluted with water (30 mL), a 1N aqueous hydrochloric acid solution(5 mL), and ethyl acetate (30 mL). The layers were separated, and theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1hexanes/ethyl acetate) afforded3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methyl-thiazol-2-yl)-propionamide(223 mg, 56%) as a pale yellow foam: mp 81-85° C. (foam to gel); [α]²³₅₈₉=−40.4° (c=1.01, chloroform); EI-HRMS m/e calcd for C₁₉H₂₄N₂O₃S₂ (M⁺)392.1228, found 392.1225.

EXAMPLE 130N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide

[0663]

[0664] A solution of diisopropylamine (3.3 mL, 23.5 mmol) in drytetrahydrofuran (50 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to−78° C. under nitrogen and then treated with a 10M solution ofn-butyllithium in hexanes (2.35 mL, 23.5 mmol). The yellow reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in asmall amount of dry tetrahydrofuran. After approximately one-half of the4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added, aprecipitate formed. Upon further addition of the remaining4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reactionmixture became thick in nature. After complete addition of the4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reactionmixture was very thick and became difficult to stir. An additionalamount of dry tetrahydrofuran (20 mL) was added to the thick reactionmixture, and the reaction mixture was then stirred at −78° C. for 45min. The reaction mixture was then treated with a solution ofiodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of drytetrahydrofuran was added dropwise. The reaction mixture was allowed towarm to 25° C. where it was stirred for 15 h. The reaction mixture wasquenched with water (100 mL), and the resulting yellow reaction mixturewas concentrated in vacuo to remove tetrahydrofuran. The aqueous residuewas acidified to pH=2 using concentrated hydrochloric acid. The aqueouslayer was extracted with ethyl acetate. The organic phase was dried overmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethylacetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionicacid (1.80 g, 52%) as a white solid: mp 152-154° C.; EI-HRMS m/e calcdfor C₁₅H₂₀O₄S (M⁺) 296.1082, found 296.1080.

[0665] A solution of3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01mmol) and dry N,N-dimethylformamide (2 drops) in methylene chloride (3mL) was cooled to 0° C. and then treated dropwise with oxalyl chloride(115 μL, 1.32 mmol). The reaction mixture was stirred at 0° C. for 10min and then stirred at 25° C. for 1 h. The reaction mixture wasconcentrated in vacuo. The resulting yellow oil was dissolved in a smallamount of methylene chloride and then slowly added to a solution of2-amino-5-chlorothiazole hydrochloride (259 mg, 1.52 mmol) andtriethylamine (424 μL, 3.04 mmol) in N,N-dimethylformamide (3 mL). Theresulting reaction mixture was then stirred at 25° C. for 15 h. Thereaction mixture was then partitioned between water (50 mL) and ethylacetate (50 mL), and the layers were separated. The aqueous layer wasback-extracted with ethyl acetate (50 mL). The combined organic layerswere then dried over magnesium sulfate, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1hexanes/ethyl acetate) afforded theN-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide(106 mg, 25%) as a tan foam: mp 76-79° C. (foam to gel); EI-HRMS m/ecalcd for C₁₈H21ClN₂O₃S₂ (M⁺) 412.0682, found 412.0683.

EXAMPLE 131N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide

[0666]

[0667] A solution of triphenylphosphine (4.60 g, 17.55 mmol) inmethylene chloride (50 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (3.12 g, 17.55 mmol). The reaction mixture wasstirred at 0° C. for 25 min and then treated with3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared asin Example 128, 4.00 g, 13.50 mmol). The resulting reaction mixture wasstirred at 0° C. for 15 min and then allowed to warm to 25° C. where itwas stirred for 30 min. The reaction mixture was then treated with asolution of 2-amino-5-chlorothiazole hydrochloride (5.77 g, 33.75 mmol)and pyridine (4.37 mL, 54.03 mmol) in methylene chloride. The resultingreaction mixture was allowed to stir at 25° C. overnight. The reactionmixture was then diluted with water (150 mL), a 1N aqueous hydrochloricacid solution (50 mL), and ethyl acetate (100 mL). The layers wereseparated. The organic layer was washed with a saturated aqueous sodiumbicarbonate solution (2×50 mL) and then dried over magnesium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) affordedN-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide(2.24 g, 40%) as a yellow foam: mp 83-88° C. (foam to gel); [α]²³₅₈₉=−73.3° (c=1, chloroform); EI-HRMS m/e calcd for C₁₈H₂₁ClN₂O₃S₂ (M⁺)412.0682, found 412.0692.

EXAMPLE 132N-(5-Bromo-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide

[0668]

[0669] A solution of3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (prepared inExample 130, 300 mg, 1.01 mmol) and dry N,N-dimethylformamide (2 drops)in methylene chloride (3 mL) was cooled to 0° C. and then treateddropwise with oxalyl chloride (115 μL, 1.32 mmol). The reaction mixturewas stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. Thereaction mixture was concentrated in vacuo. The resulting yellow oil wasdissolved in a small amount of methylene chloride and then slowly addedto a solution of 2-amino-5-bromothiazole monohydrobromide (395 mg, 1.52mmol) and triethylamine (424 μL, 3.04 mmol) in N,N-dimethylformamide (3mL). The resulting reaction mixture was then stirred at 25° C. for 15 h.The resulting reaction mixture was partitioned between water (50 mL) andethyl acetate (50 mL), and the layers were separated. The aqueous layerwas further extracted with ethyl acetate (50 mL). The combined organiclayers were then dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1/1 hexanes/ethyl acetate) afforded theN-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide(160 mg, 35%) as a tan foam: mp 73-75° C. (foam to gel); EI-HRMS m/ecalcd for C₁₈H₂₁BrN₂O₃S₂ (M⁺) 456.0177, found 456.0176.

EXAMPLE 133N-(5-Bromo-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide

[0670]

[0671] A solution of triphenylphosphine (3.35 g, 12.79 mmol) inmethylene chloride (19 mL) was cooled to 0° C. and then slowly treatedwith N-bromosuccinimide (2.28 g, 12.79 mmol) in small portions. Thereaction mixture was stirred at 0° C. for 30 min, and during this timeperiod, the color of the reaction mixture changed from light yellow to adarker yellow then to a purple color. The cooled purple reaction mixturewas then treated with3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared asin Example 128, 2.23 g, 7.52 mmol). The resulting reaction mixture wasthen allowed to warm to 25° C. over 45 min. The reaction mixture wasthen treated with 2-aminothiazole (1.88 g, 18.81 mmol). The resultingreaction mixture was stirred at 25° C. for 12 h. The reaction mixturewas then concentrated in vacuo to remove methylene chloride. Theremaining black residue was diluted with ethyl acetate (300 mL). Theorganic layer was washed sequentially with a 10% aqueous hydrochloricacid solution (2×100 mL), a 5% aqueous sodium bicarbonate solution(3×100 mL), and a saturated aqueous sodium chloride solution (1×200 mL).The organic layer was then dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate) afforded3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide(2.10 g, 74%) as a white foam: mp 78-80° C. (foam to gel); [α]²³₅₈₉=−70.4° (c=0.027, chloroform); EI-HRMS m/e calcd for C₁₈H₂₂N₂O₃S₂(M⁺) 378.1072, found 378.1081.

[0672] A suspension of3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(1.0 g, 2.64 mmol) and N-bromosuccinimide (470 mg, 2.64 mmol) in carbontetrachloride (5 mL) at 25° C. was treated with benzoyl peroxide (32 mg,0.132 mmol). The resulting reaction mixture was heated to 90° C. whereit was stirred at this temperature overnight. The reaction mixture wasallowed to cool to 25° C. and then concentrated in vacuo. The resultingresidue was dissolved in ethyl acetate (60 mL). The organic phase wasthen washed with water (1×100 mL) and a saturated aqueous sodiumchloride solution (1×100), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M,Silica, 2/1 to 1/1 hexanes/ethyl acetate) affordedN-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide(546 mg, 45%) as an amorphous solid: EI-HRMS m/e calcd forC₁₈H₂₁BrN₂O₃S₂ (M⁺) 456.1077, found 456.1077.

EXAMPLE 134 2-3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylaminol-thiazole-5-carboxylic Acid Amide

[0673]

[0674] A solution of diisopropylamine (3.2 mL, 23.16 mmol) in drytetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooledto −78° C. under nitrogen and then treated with a 10M solution ofn-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) indry tetrahydrofuran (10.3 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). Thereaction mixture was allowed to stir at −78° C. for 1 h, at which time,a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a smallamount of dry tetrahydrofuran was added dropwise. The reaction mixturewas then stirred at −78° C. for 30 min and then allowed to warm to 25°C. where it was stirred for 24 h. The reaction mixture was quenched withwater and then concentrated in vacuo to remove tetrahydrofuran. Theremaining aqueous phase was acidified to pH=2 with a 10% aqueoushydrochloric acid solution and then extracted with ethyl acetate (200mL). The organic layer was washed with a saturated aqueous sodiumchloride solution (1×100 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 3/1 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) asa cream solid: mp 91-93° C.; EI-HRMS m/e calcd for C₁₅H₂₀O₂S (M⁺)264.1184, found 264.1177.

[0675] A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionicacid (2.54 g, 9.60 mmol) in formic acid (7 mL) was cooled to 0° C. andthen treated with a 30% aqueous hydrogen peroxide solution (8.3 mL, 20.0mmol). The resulting solution was allowed to warm to 25° C. where it wasstirred for 1 h. The reaction was then re-cooled to 0° C., and theproduct was precipitated by the addition of water (30 mL). The solid wasfiltered off and dried to afford pure3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (2.48 g, 87%) asa white solid which was used without further purification: mp 154-159°C.; EI-HRMS m/e calcd for C₁₅H₂₀O₄S (M⁺) 296.1082, found 296.1080.

[0676] A solution of3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (717 mg, 1.62 mmol), triethylamine (420 μL, 3.03mmol), and 2-amino-thiazole-5-carboxylic acid ethyl ester: (279 mg, 1.62mmol) in methylene chloride (10 mL) was stirred at 25° C. under nitrogenfor 14 h. The reaction mixture was partitioned between water andmethylene chloride. The organic layer was sequentially washed with a 1Naqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and asaturated aqueous sodium bicarbonate solution (1×10 mL). The organiclayer was dried over magnesium sulfate, filtered, and concentrated invacuo. Biotage chromatography (FLASH 40S, Silica, 10/11 hexanes/ethylether) afforded2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylicacid ethyl ester (448 mg, 98%) as a white solid: mp 100-103° C.; EI-HRMSm/e calcd for C₂₁H₂₆N₂O₅S₂(M⁺) 450.1283, found 450.1285.

[0677] A solution of2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylicacid ethyl ester (430 mg, 0.95 mmol) in ethanol (10 mL) and water (2 mL)was treated with lithium hydroxide (46 mg, 1.9 mmol). The reactionmixture was stirred at 25° C. for 14 h. The reaction mixture was thenconcentrated in vacuo to remove methanol. The resulting aqueous residuewas diluted with water (20 mL) and then washed ethyl acetate (1×20 mL).The aqueous layer was then acidified to pH=2 with a 10% aqueoushydrochloric acid solution and then extracted with ethyl acetate (3×40mL). The combined organic layers were then dried over magnesium sulfate,filtered, and concentrated in vacuo to afford2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylicacid (386 mg, 96%) as a white solid which was used without furtherpurification: mp 172-176° C.

[0678] A solution of2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylicacid (100 mg, 0.24 mmol) in dry tetrahydrofuran (3 mL) under argon wastreated with N-methylmorpholine (0.04 mL, 0.36 mmol) followed byiso-butylchloroformate (50 μL, 0.36 mmol). The reaction was stirred at25° C. for 2 h, after which time, a concentrated aqueous ammoniumhydroxide solution (0.2 mL) was added. The resulting reaction mixturewas stirred at 25° C. for 2 h. The reaction mixture was then treatedwith water (5 mL), and the tetrahydrofuran was concentrated in vacuo.The product was then extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 9/1 chloroform/methanol) afforded2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylicacid amide (68 mg, 67%) as a white solid: mp 155-160° C.; EI-HRMS m/ecalcd for C₁₉H₂₃N₃O₄S₂(M⁺) 421.1130, found 421.1135.

EXAMPLE 1353-Cyclopentyl-2-(3-fluro-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0679]

[0680] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methylester (prepared as in Example 14, 1.50 g, 4.22 mmol) in methanol (30 mL)was treated with a solution of ammonium chloride (474 mg, 8.86 mmol) inwater (3 mL). The reaction mixture was stirred at 25° C. for 5 min andthen treated with zinc dust (2.70 g, 41.36 mmol). The reaction mixturewas heated under reflux for 2 h. The reaction mixture was allowed tocool to 25° C. and then filtered through a pad of celite. The filtratewas concentrated in vacuo. The resulting orange oil was dissolved inethyl acetate, dried over magnesium sulfate, filtrated, and concentratedin vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1hexanes/ethyl acetate) afforded2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (1.49 g, 98%) as a white solid: mp 98-100° C.; EI-HRMS m/e calcdfor C₁₆H₂₃NO₄S (M⁺) 325.1348, found 325.1358.

[0681] A slurry of nitrosonium tetrafluoroborate (215 mg, 1.84 mmol) inmethylene chloride (6 mL) was cooled to 0° C. and then treated dropwisewith a solution of2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (500 mg, 1.54 mmol) in a small amount of methylene chloride. Theresulting reaction mixture was stirred at 0° C. for 1 h. The reactionmixture was then allowed to warm to 25° C. and was treated with1,2-dichlorobenzene (6 mL). The resulting reaction mixture was heated at100° C. for 1 h, during which time, the methylene chloride was distilledoff. After 1 h at 100° C., the reaction mixture was allowed to cool to25° C. The crude reaction mixture was directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethylacetate to elute 1,2-dichlorobenzene then 2/1 hexanes/ethyl acetate) toafford impure3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acidmethyl ester as a yellow oil. Repurification by flash chromatography(Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) affordedpure 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acidmethyl ester (214 mg, 42%) as a pale yellow oil which solidified uponsitting at 25° C. to a pale yellow solid: mp 66-68° C.; EI-HRMS m/ecalcd for C₁₆H₂₁FO₄S (M⁺) 328.1144, found 328.1148.

[0682] A solution of3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acidmethyl ester (110 mg, 0.335 mmol) in tetrahydrofuran (1 mL) was treatedwith a 0.8M aqueous lithium hydroxide solution (630 μL, 0.502 mmol). Thereaction mixture was stirred at 25° C. for 2 h and then treated withwater (30 mL), a 1N aqueous hydrochloric acid solution (2 mL), and ethylacetate (30 mL). The layers were separated, and the resulting aqueouslayer was back-extracted with ethyl acetate (30 mL). The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid as apale yellow oil which solidified to a pale yellow solid upon sitting at25° C. The pale yellow solid corresponding to3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (106mg, 98%) was used without further purification: mp 115-117° C.; EI-HRMSm/e calcd for C₁₅H₁₉FO₄S (M⁺) 314.0988, found 314.0986.

[0683] A solution of triphenylphosphine (48 mg, 0.183 mmol) in methylenechloride (700 μL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (33 mg, 0.183 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (50mg, 0.159 mmol). The resulting reaction mixture was stirred at 0° C. for5 min and then allowed to warm to 25° C. where it was stirred for 30min. The reaction mixture was then treated with 2-aminothiazole (35 mg,0.35 mmol). The resulting reaction mixture was stirred at 25° C. for 15h. The crude reaction mixture was directly purified by flashchromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethylacetate) to afford3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(40.4 mg, 64%) as a pink solid: mp 200-202° C.; EI-HRMS m/e calcd forC₁₈H₂₁FN₂O₃S₂ (M⁺) 396.0978, found 396.0976.

EXAMPLE 1363-Cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide

[0684]

[0685] A solution of triphenylphosphine (48 mg, 0.183 mmol) in methylenechloride (700 μL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (33 mg, 0.183 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid(prepared as in Example 135, 50 mg, 0.159 mmol). The resulting reactionmixture was stirred at 0° C. for 5 min and then allowed to warm to 25°C. where it was stirred for 30 min. The reaction mixture was thentreated with 2-aminopyridine (33 mg, 0.35 mmol). The resulting reactionmixture was stirred at 25° C. for 15 h. The crude reaction mixture wasdirectly purified by flash chromatography (Merck Silica gel 60, 230-400mesh, 2/1 hexanes/ethyl acetate) to afford3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide(23.7 mg, 38%) as a pink solid: mp 76-79° C.; EI-HRMS m/e calcd forC₂₀H₂₃FN₂O₃S (M⁺) 390.1413, found 390.1420.

EXAMPLE 137N-(5-Bromo-thiazol-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

[0686]

[0687] A solution of aluminum trichloride (54.9 g, 412 mmol) inchloroform (180 mL) under argon was cooled to 0° C. and then treateddropwise with a solution of methyl chlorooxoacetate (24.3 mL, 264 mmol)in chloroform (180 mL). The reaction mixture was stirred at 0° C. for 30min and then was treated dropwise with a solution of 2-chlorothioanisole(39.4 g, 247 mmol) in chloroform (180 mL). The reaction mixture turnedred in color. The resulting reaction mixture was allowed to warm to 25°C. where it was stirred for 4 h. The reaction mixture was then slowlypoured onto ice (700 mL). The resulting yellow mixture was stirred for15 min and then was filtered through celite to remove the aluminumsalts. The filtrate was then extracted with methylene chloride (3×50mL). The combined organic layers were washed with a saturated aqueoussodium bicarbonate solution (1×50 mL). The organic layer was then driedover magnesium sulfate, filtered, and concentrated in vacuo to afford(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid methyl ester (36.4 g,60%) as a light yellow oil: EI-HRMS m/e calcd for C₁₀H₉ClSO₃ (M⁺)243.9961, found 243.9958.

[0688] A solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acidmethyl ester (61.7 g, 252 mmol) in toluene (120 mL) was heated at 50° C.This heated solution was then treated dropwise with a 3M aqueous sodiumhydroxide solution (105 mL, 313 mmol) via a dropping funnel, taking careto keep the temperature below 60° C. After the addition was complete,the reaction mixture was stirred at 50° C. for another 1.5 h, duringwhich time, a yellow precipitate began to form. After this time, theheat was removed, and the warm solution was treated dropwise withconcentrated hydrochloric acid (10.6 mL, 290 mmol). The resultingreaction mixture was allowed to cool to 25° C. and then was stirred at25° C. for 16 h. The solid was filtered and then washed with water (50mL) and toluene (50 mL). The solid was dried by suction for 1 h and thendried in a high vacuum desiccator to afford(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid (57.22 g, 98%) as awhite solid: mp 166° C. (dec); FAB-HRMS m/e calcd for C₉H₇ClSO₃ (M+Na)⁺252.9702, found 252.9700.

[0689] A reaction flask equipped with mechanical stirrer was chargedwith hydrazine hydrate (8.5 mL, 273 mmol). The hydrazine hydrate wascooled to −50° C. and then treated with(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid (12.6 g, 54.6 mmol)in one portion. An exotherm ensued that raised the temperature. Theresulting white milky mixture was then heated to 80° C. After reaching80° C., the heating element was removed, and the reaction mixture wasthen treated with potassium hydroxide (2.09 g, 31.7 mmol) in oneportion. An exotherm was observed. The reaction was then stirred at 25°C. until the reaction temperature cooled back to 80° C. At this time,another portion of potassium hydroxide (2.09 g, 31.7 mmol) was added.Again, an exotherm was observed, and the resulting reaction mixture wasallowed to cool back to 80° C. Once at 80° C., a third portion ofpotassium hydroxide (2.09 g, 31.7 mmol) was added to the reactionmixture. Another exotherm was observed, and after cooling back to 80°C., the fourth and final portion of potassium hydroxide (2.09 g, 31.7mmol) was added. At this point, the heating element was added, and thereaction mixture was heated at 100° C. for 16 h. The resultinghomogenous reaction mixture was cooled to 25° C. and then diluted withwater (12 mL). The reaction mixture was then transferred to a separatoryfunnel, rinsing with additional water (12 mL) and diethyl ether (40 mL).The layers were separated, and the aqueous layer was transferred to aflask. The organic layer was extracted with water (2×15 mL) The aqueouslayers were combined and treated with heptane (20 mL), and the resultingreaction mixture was vigourously stirred. This stirred solution was thentreated dropwise with concentrated hydrochloric acid (26 mL) over 30 minwhile the temperature was kept under 50° C. with an ice bath. A cloudysuspension formed, and this suspension was stirred at 25° C. for 3 h.The solid that formed was collected by filtration and then washedsequentially with a 1N aqueous hydrochloric acid solution (2×6 mL),heptane (1×12 mL), and a solution of heptane/diethyl ether (15 mL, 4:1).The resulting solid was dried under high vacuum to afford(3-chloro-4-methylsulfanyl-phenyl)-acetic acid (10.48 g, 89%) as anoff-white solid: mp 105.6-108.4° C.; EI-HRMS m/e calcd for C₉H₉ClSO₂(M⁺) 216.0012, found 216.0022.

[0690] A mixture of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid(10.48 g, 48.4 mmol) and potassium carbonate (20.1 g, 145.1 mmol) inacetone (65 mL) was cooled to −10° C. The pale yellow slurry was thentreated dropwise with trimethylacetyl chloride (6.25 mL, 50.8 mmol)while maintaining the temperature below −10° C. The resulting reactionmixture was stirred at −10° C. for 15 min and then allowed to warm to 0°C. where it was stirred for 10 min. The reaction mixture was re-cooledto −10° C. and then treated with (1R, 2R)-(−)-pseudoephedrine (11.99 g,72.5 mmol), resulting in an exotherm. The reaction mixture was stirred−10° C. for 10 min and then warmed to 25° C. where it was stirred for 1h. After such time, thin layer chromatography analysis indicated thatthe reaction was complete. The reaction mixture was then quenched withwater (50 mL) and then extracted with ethyl acetate (1×100 mL). Theorganic layer was washed with water (2×40 mL). The aqueous layers werecombined and back-extracted with ethyl acetate (2×50 mL). The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was recrystallized from ethylacetate (45 mL) and hexanes (80 mL) to afford2-(3-chloro-4-methylsulfanyl-phenyl)-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-acetamide(13.75 g, 78%) as a light yellow solid: mp 111.5-112.9° C.; [α]²³₅₈₉=−97.2° (c=0.104, chloroform); FAB-HRMS m/e calcd for C₁₉H₂₂ClNSO₂(M+H)⁺ 364.1138, found 364.1142.

[0691] A solution of 1,1,1,3,3,3-hexamethyldisilazane (17.9 mL, 85 mmol)in tetrahydrofuran (90 mL) was cooled to −78° C. and then treated with a2.34M solution of n-butyllithium in hexanes (33.9 mL, 79.3 mmol). Thereaction mixture was stirred at −78° C. for 15 min and then slowlytreated with a solution of2-(3-chloro-4-methylsulfanyl-phenyl)-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-acetamide(13.75 g, 37.8 mmol) in tetrahydrofuran (90 mL) while maintaining thetemperature below −65° C. The resulting yellow-orange reaction mixturewas stirred at −78° C. for 15 min and then allowed to warm to 0° C.where it was stirred for 20 min. The reaction mixture was then re-cooledto −78° C. and then treated with a solution of iodomethylcyclopentane(11.9 g, 56.7 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (9.6 mL, 79.3 mmol).The resulting reaction mixture was stirred at −78° C. for 30 min andthen allowed to warm to 25° C. where it was stirred for 16 h. Thereaction mixture was diluted with ethyl acetate (200 mL) and then washedwith a saturated aqueous ammonium chloride solution (1×100 mL). Theaqueous layer was then extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with a saturated aqueous sodiumchloride solution (1×50 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. The resulting material was then re-dissolved inethyl acetate. This organic phase was washed with a 10% aqueous sulfuricacid solution (2×100 mL) and a 10% aqueous sodium bicarbonate solution(2×100 mL), dried over magnesium sulfate, filtered, and concentrated invacuo. The crude material was recrystallized from ethyl acetate/hexanesto afford2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-propionamide(11.36 g, 67%) as a light yellow solid: mp 113.8-117.6° C.; [α]²³₅₈₉=−100.3° (c=0.09, chloroform); FAB-HRMS m/e calcd for C₂₅H₃₂ClNSO₂(M−H)⁺ 444.1764, found 444.1765.

[0692] A solution of2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-propionamide(11.36 g, 25.5 mmol) in dioxane (45 mL) was treated with a 9N aqueoussulfuric acid solution (28 mL). The resulting reaction mixture was thenheated at 105° C. for 16 h. The reaction mixture was then cooled to 0°C. with an ice bath, and the product was precipitated by adding water(200 mL). The suspension was stirred at 0° C. until the supernatant,which was initially turbid, became clear and light yellow in color. Thesolid was filtered off and dried by suction. The solid material wasdissolved in hot glacial acetic acid (15 mL), and the hot solution wastreated with water (10 mL) to initiate crystallization. The mixture wasallowed to cool to 25° C. and then treated with an additional amount ofwater (20 mL). After stirring at 25° C. for 1 h, the solid was collectedby filtration. The solid was dried in a high vacuum desiccator withphosphourous pentoxide to afford2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid(7.46 g, 98%) as a white solid: mp 116.9-119.2° C.; [α]²³ ₅₈₉=−55.8°(c=0.104, chloroform); EI-HRMS m/e calcd for C₁₅H₁₉ClSO₂ (M)⁺ 298.0794,found 298.0804.

[0693] A slurry of2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid(15.68 g, 52.5 mmol) in formic acid (10 mL) was cooled to 0° C. and thentreated with a 30% aqueous hydrogen peroxide solution (30 mL). Theresulting solution was allowed to warm to 25° C. where it was stirredfor 16 h. The product was precipitated by the addition of water (120mL). The solid was filtered off, washed with water, and dried bysuction. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50hexanes/ethyl acetate plus 1% acetic acid) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(13.93 g, 80%) as a white solid: mp 123.9-126.2° C.; [α]²³ ₅₈₉=−41.5°(c=0.176, chloroform); FAB-HRMS m/e calcd for C₁₅H₁₉ClO₄S (M+H)⁺331.0771, found 331.0776.

[0694] A solution of triphenylphosphine (595 mg, 2.27 mmol) in methylenechloride (20 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (457 mg, 2.57 mmol). The reaction mixture was stirredat 0° C. until it became homogeneous. The resulting light purplereaction mixture was then treated with2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(500 mg, 1.51 mmol). The reaction mixture was stirred at 0° C. for 20min and then allowed to warm to 25° C. where it was stirred for 30 min.The reaction mixture was then treated with 2-amino-5-bromothiazolemonohydrobromide (589 mg, 2.27 mmol) and pyridine (0.37 mL, 4.53 mmol),and then the reaction mixture was stirred at 25° C. for 16 h.

[0695] The reaction was then diluted with water (15 mL) and thenextracted with methylene chloride (3×15 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate)affordedN-(5-bromo-thiazol-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide(375 mg, 51%) as a light green foam: [α]²³ ₅₈₉=−110.3° (c=0.068,chloroform); EI-HRMS m/e calcd for C₁₈H₂₀ClBrN₂O₃S₂ (M⁺) 489.9787, found489.9792.

EXAMPLE 1382(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-thiazol-2-yl)-propionamide

[0696]

[0697] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (6 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it became homogeneous. The resulting light purplereaction mixture was then treated with2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixturewas stirred at 0° C. for 20 min and then allowed to warm to 25° C. whereit was stirred for 30 min. The reaction mixture was then treated with2-amino-5-methylthiazole (104 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82mmol), and the resulting reaction mixture was stirred at 25° C. for 16h. The reaction was then diluted with water (15 mL) and then extractedwith methylene chloride (3×15 mL). The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-thiazol-2-yl)-propionamide(201 mg, 78%) as a orange foam: [α]²³ ₅₈₉=−72.7° (c=0.055, chloroform);EI-HRMS m/e calcd for C₁₉H₂₃ClN₂O₃S₂(M⁺) 426.0838, found 426.0837.

EXAMPLE 1392(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(4-methyl-thiazol-2-yl)-propionamide

[0698]

[0699] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (6 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it became homogeneous. The resulting light purplereaction mixture was then treated with2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixturewas stirred at 0° C. for 20 min and then allowed to warm to 25° C. whereit was stirred for 30 min. The reaction mixture was then treated with2-amino-4-methylthiazole (104 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82mmol), and the resulting reaction mixture was stirred at 25° C. for 16h. The reaction was then diluted with water (15 mL) and then extractedwith methylene chloride (3×15 mL). The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(4-methyl-thiazol-2-yl)-propionamide(118 mg, 46%) as an off-white foam: [α]²³ ₅₈₉=−44.4° (c=0.024,chloroform); EI-HRMS m/e calcd for C¹⁹H₂₃ClN₂O₃S₂(M⁺) 426.0838, found426.0837.

EXAMPLE 1402(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-propionamide

[0700]

[0701] A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylenechloride (10 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirredat 0° C. until it became homogeneous. The resulting light purplereaction mixture was then treated with2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixturewas stirred at 0° C. for 20 min and then allowed to warm to 25° C. whereit was stirred for 30 min. The reaction mixture was then treated with2-amino-5-picoline (98.1 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82mmol), and the reaction mixture was stirred at 25° C. for 16 h. Thereaction was then diluted with water (15 mL) and then extracted withmethylene chloride (3×15 mL). The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-propionamide(197 mg, 77%) as a white foam: [α]²³ ₅₈₉=−47.8° (c=0.046, chloroform);EI-HRMS m/e calcd for C₂₁H₂₅ClN₂O₃S (M⁺) 420.1274, found 420.1273.

EXAMPLE 1412-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide

[0702]

[0703] A solution of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 143, 50 mg, 0.15 mmol) in methylene chloride(1.5 mL) was treated with N,N-dimethylformrnamide (1 drop) and thencooled to 0° C.. The reaction mixture was then treated dropwise with a2M solution of oxalyl chloride in methylene chloride (0.11 mL, 0.23mmol) and stirred at 0° C. for 30 min. The reaction mixture was thentreated with a solution of 4-aminopyrimidine (29 mg, 0.30 mmol) andpyridine (0.06 mL, 0.76 mmol) in tetrahydrofuran (2.5 mL). The resultingreaction mixture was allowed to warm to 25° C. where it was stirred for16 h. The reaction mixture was then diluted with water (10 mL) andextracted with ethyl acetate (3×15 mL). The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 20/80 hexanes/ethyl acetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-2-yl-propionamide(47 mg, 76%) as a white foam: EI-HRMS m/e calcd for C₁₉H₂₂ClN₃O₃S (M⁺)407.1070, found 407.1080.

EXAMPLE 1422(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide

[0704]

[0705] A solution of2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 137, 200 mg, 0.61 mmol) in methylene chloride (5mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to0° C. The reaction mixture was then treated dropwise with a 2M solutionof oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) andstirred at 0° C. for 30 min. The reaction mixture was then treated witha solution of 4-aminopyrimidine (115 mg, 1.21 mmol) and pyridine (0.245mL, 3.03 mmol) in tetrahydrofuran (10 mL). The resulting reactionmixture was allowed to warm to 25° C. where it was stirred for 16 h. Thereaction mixture was then diluted with water (10 mL) and extracted withmethylene chloride (3×15 mL). The combine organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 20/80 hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide(105 mg, 43%, 80% R-isomer) as a white foam: [α]²³ ₅₈₉=−38.0° (c=0.050,chloroform); EI-HRMS m/e calcd for C₁₉H₂₂ClN₃O₃S (M⁺) 407.1070, found407.1072.

EXAMPLE 1432-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0706]

[0707] A mixture of acetamidine hydrochloride (2.00 g, 21.2 mmol) in a0.5M solution of sodium methoxide in methanol (42.3 mL, 21.2 mmol) wasstirred at 25° C. for 30 min. After this time, the sodium chloride wascollected by filtration, and the filtrate was concentrated in vacuo. Theresulting residue was diluted with 3-ethoxyacrylonitrile (2.18 ml, 21.2mmol), and the reaction mixture was heated at 160° C. for 3 h. Afterthis time, ethanol evolution stopped, and the melt began to crystallize.The red-brown solution was cooled to 25° C. A small amount of methanolwas added, and the solid was filtered. The solid was then washed withmethanol to afford 4-amino-2-methylpyrimidine (1.03 g, 44%) as anoff-white solid: mp >200° C.; EI-HRMS m/e calcd for C₅H₇N₃ (M⁺)109.0640, found 109.0640.

[0708] A solution of aluminum chloride (34.8 g, 261.4 mmol) inchloroform (120 mL) under argon was cooled to 0° C. and then treateddropwise with a solution of ethyl oxalyl chloride (18.7 mL, 167.5 mmol)in chloroform (120 mL). The reaction mixture was stirred at 0° C. for 30min and then treated dropwise with a solution of 2-chlorothioanisole(25.0 g, 156.5 mmol) in chloroform (120 mL). The resulting reactionmixture turned red in color. The reaction mixture was allowed to warm to25° C. where it was stirred for an additional 3.5 h. The reactionmixture was then slowly quenched with water (500 mL), and upon additionof the water, the reaction mixture turned yellow in color. The resultingsolution was then extracted with chloroform (3×50 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 80/20 hexanes/ethyl acetate) afforded(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (31.37 g,77%) as a yellow oil.

[0709] A solution of iodomethylcyclopentane (129.38 g, 0.616 mol) andtriphenylphosphine (161.54 g, 0.616 mol) in acetonitrile (308 mL) washeated under reflux for 9 d. The reaction mixture was allowed to cool to25° C. and then concentrated in vacuo to provide a solid. The solid wastriturated with diethyl ether and then filtered. The solid was washedwell with diethyl ether until the washings showed the absence ofiodomethylcyclopentane and triphenylphosphine by thin layerchromatography. The resulting solid was allowed to air dry to affordcyclopentylmethyl triphenylphosphonium iodide (266.92 g, 92%) as a lightyellow solid: mp 195-198° C.; FAB-HRMS m/e calcd for C₂₄H₂₆P (M+H)⁺345.1772, found 345.1784.

[0710] A suspension of cyclopentylmethyl triphenylphosphine iodide (725mg, 1.53 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and thentreated with a 1.0M solution of sodium bis(trimethylsilyl)amide intetrahydrofuran (2.14 mL, 2.14 mmol). The resulting red reaction mixturewas stirred at 0° C. for 45 minutes and then slowly treated with asolution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethylester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reactionmixture was warmed to 25° C. where it was stirred for 20 h. The reactionmixture was then diluted with water (50 mL) and extracted with diethylether (3×25 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Biotage chromatography(Flash 12M, Silica, 80/20 hexanes/ethyl acetate) afforded2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (267 mg, 60%) as a yellow oil consisting of a 2:1 mixture of(E):(Z) isomers. The isomeric mixture was used without furtherseparation and characterization.

[0711] A solution of the isomeric mixture of2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (100 mg, 0.31 mmol) in methylene chloride (5 mL) was cooled to 0°C. and then treated with 3-chloroperoxybenzoic acid (80% grade, 157 mg,0.729 mmol). The reaction mixture was stirred at 0° C. for 3.5 h andthen diluted with methylene chloride (25 mL). The organic phase waswashed with a saturated aqueous sodium carbonate solution (2×10 mL) anda saturated aqueous sodium chloride solution (2×10 mL). The organiclayer was dried over sodium sulfate, filtered, and concentrated invacuo. Biotage chromatography (Flash 12M, Silica, 80/20 hexanes/ethylacetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (95 mg, 86%) as a colorless oil consisting of a 2:1 mixture of(E):(Z) isomers. The isomeric mixture was used without furtherseparation and characterization.

[0712] A solution of the isomeric mixture of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid ethylester (1.04 g, 2.91 mmol) and nickel chloride hexahydrate (69 mg, 0.29mmol) in methanol (25 mL) was slowly treated with sodium borohydride(221 mg, 5.83 mmol) in small portions. If necessary, an ice bath wasused to keep the temperature at 20° C. The initial green solution turnedblack in color, and a fine precipitate formed after addition of thesodium borohydride. The reaction mixture was then stirred at 25° C. for1.5 h. The reaction mixture was then filtered through celite and washedwith methanol. The filtrate and washings were combined and concentratedin vacuo to reduce the volume. The residual solution was then dilutedwith water (15 mL) and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 75/25 hexanes/ethyl acetate) afforded a mixture of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acidmethyl ester and2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethylester (937 mg, transesterification occurred under the reactionconditions) as a clear colorless oil. This mixture was used withoutfurther separation and characterization.

[0713] The mixture of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acidmethyl ester and2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethylester (937 mg) was dissolved in ethanol (30 mL). This solution was thentreated with a solution of potassium hydroxide (733 mg, 13.1 mmol) inwater (7 mL). The resulting yellow solution was stirred at 25° C. for 3h and then concentrated in vacuo to remove ethanol. The aqueous residuewas treated with a 1N aqueous hydrochloric acid solution until the pH=2.The product was then extracted into methylene chloride (3×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (787mg, 82% for two steps) as a white solid: mp 123.9-126.2° C.; FAB-HRMSm/e calcd for C₁₅H₁₉ClO₄S (M+H)⁺ 331.0771, found 331.0776.

[0714] A solution of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200mg, 0.61 mmol) in methylene chloride (2 mL) was treated withN,N-dimethylformamide (1 drop) and then cooled to 0° C. The reactionmixture was then treated dropwise with a 2M solution of oxalyl chloridein methylene chloride (0.45 mL, 0.91 mmol) and stirred at 0° C. for 30min. The resulting reaction mixture was then treated with a solution of4-amino-2-methylpyrimidine (98.9 mg, 0.91 mmol) and pyridine (0.25 mL,3.03 mmol) in N,N-dimethylformamide (5 mL). The resulting reactionmixture was allowed to warm to 25° C. where it was stirred for 16 h. Thereaction mixture was then diluted with water (10 mL) and extracted withethyl acetate (3×15 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide(64 mg, 25%) as a colorless oil: EI-HRMS m/e calcd for C₂₀H₂₄ClN₃O₃S(M⁺) 421.1227, found 421.1230.

EXAMPLE 1442(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0715]

[0716] A slurry of 4-amino-2-methylpyrimidine (2.04 g, 18.69 mmol) in1,1,1,3,3,3-hexamethyldisilazane (40 mL) and chlorotrimethylsilane (0.36mL, 2.8 mmol) was heated at 150° C. for 8 h. At this time, the reactionmixture was close to a homogeneous solution. The resulting slightlyorange solution was then filtered to remove any remaining solids. Thefiltrate was concentrated in vacuo to afford4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-2-methyl-pyrimidine as anoff-white solid (2.18 g).

[0717] A solution of2(R)-(3-chloro-4-methanesulfanyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 137, 1.20 g, 4.02 mmol) in methylene chloride (5mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to0° C. The reaction mixture was then treated dropwise with a 2M solutionof oxalyl chloride in methylene chloride (2.21 mL, 4.42 mmol) andstirred at 0° C. for 30 min. The resulting reaction mixture was thentreated with a solution of the4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-2-methyl-pyrimidine (2.04 g,8.03 mmol) and pyridine (1.3 mL, 16.06 mmol) in tetrahydrofuran (25 mL).The resulting reaction mixture was allowed to warm to 25° C. where itwas stirred for 16 h. The reaction mixture was then diluted withmethylene chloride (30 mL) and then washed with a 1N aqueoushydrochloric acid solution (30 mL). The aqueous layer was back-extractedwith methylene chloride (3×30 mL). The combined organic layers werewashed with a saturated aqueous sodium chloride solution (1×30 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40M, Silica, 60/40 hexanes/ethyl acetate) affordedthe2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide(1.11 g, 71%) as an off-white foam: [α]²³ ₅₈₉=−65.7° (c=0.067,chloroform).

[0718] A solution of2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide(119 mg, 0.31 mmol) in methanol (7 mL) was treated with a solution ofsodium periodate (117 mg, 0.55 mmol) in water (3.5 mL). The resultingreaction mixture was stirred at 25° C. for 8 h. After this time, theprecipitate was filtered and washed with methylene chloride (15 mL). Theorganic layer was separated and set aside. The aqueous layer wasextracted with methylene chloride (3×15 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo toafford the sulfoxide product (123 mg) which was used without furtherpurification. The resulting crude sulfoxide was dissolved in methanol (5mL) at 25° C. This solution was then treated with a solution ofpotassium permanganate (57 mg, 0.36 mmol) in water (1.5 mL), and thereaction mixture was stirred at 25° C. for 30 min. The reaction mixturewas then filtered, and the cake was washed with methylene chloride (10mL). The filtrate was then washed with a saturated aqueous sodiumbicarbonate solution (1×10 mL) and a saturated aqueous sodium chloridesolution (1×10 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 50/50hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide(65mg, 51% for two steps) as a white foam: [α]²³ ₅₈₉=−40.3° (c=0.062,chloroform); EI-HRMS m/e calcd for C₂₀H₂₄ClN₃O₃S (M⁺) 421.1227, found421.1224.

EXAMPLE 1452(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide

[0719]

[0720] A solution of2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 137, 200 mg, 0.61 mmol) in methylene chloride (4mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to0° C. The reaction mixture was then treated dropwise with a 2M solutionof oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) andstirred at 0° C. for 30 min. The resulting reaction mixture was thentreated with a solution of cytosine (101 mg, 0.91 mmol) and pyridine(0.245 mL, 3.03 mmol) in N,N-dimethylformamide (10 mL). The resultingreaction mixture was allowed to warm to 25° C. where it was stirred for16 h. The reaction mixture was then diluted with water (10 mL) andextracted with ethyl acetate (3×15 mL). The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 95/5 methylene chloride/methanol)afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide(145 mg, 57%) as a white solid: mp >200° C.; EI-HRMS m/e calcd forC₁₉H₂₂ClN₃O₄S (M⁺) 423.1019, found 423.1015.

EXAMPLE 1462-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide

[0721]

[0722] A solution of2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 143, 50 mg, 0.15 mmol) in methylene chloride (2mL) was treated with N,N-dimethylforrnamide (1 drop) and then cooled to0° C. The reaction mixture was then treated dropwise with a 2M solutionof oxalyl chloride in methylene chloride (0.11 mL, 0.23 mmol) andstirred at 0° C. for 30 min. The reaction mixture was then treated witha solution of 2-aminopyrazine (29 mg, 0.30 mmol) and pyridine (0.06 mL,0.76 mmol) in tetrahydrofuran (2.5 mL). The resulting reaction mixturewas allowed to warm to 25° C. where it was stirred for 16 h. Thereaction mixture was then diluted with water (10 mL) and extracted withethyl acetate (3×15 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 50/50 hexanes/ethyl acetate) afforded2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide(53 mg, 86%) as a white foam: EI-HRMS m/e calcd for C₁₉H₂₂ClN₃O₃S (M⁺)407.1070, found 407.1073.

EXAMPLE 1472(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide

[0723]

[0724] A solution of2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 137, 200 mg, 0.61 mmol) in methylene chloride (5mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to0° C. The reaction mixture was then treated dropwise with a 2M solutionof oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) andstirred at 0° C. for 30 min. The reaction mixture was then treated witha solution of 2-aminopyrazine (115 mg, 1.21 mmol) and pyridine (0.245mL, 3.03 mmol) in tetrahydrofuran (10 mL). The resulting reactionmixture was allowed to warm to 25° C. where it was stirred for 16 h. Thereaction mixture was then diluted with water (10 mL) and extracted withmethylene chloride (3×15 mL). The combine organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 50/50 hexanes/ethyl acetate) afforded2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide(172 mg, 70%) as a white foam: [α]²³ ₅₈₉=−46.8° (c=0.047, chloroform);El-HRMS m/e calcd for C₁₉H₂₂ClN₃O₃S (M⁺) 407.1070, found 407.1068.

EXAMPLE 1482-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide

[0725]

[0726] A solution of 4-(methylthio)phenylacetic acid (6.91 g, 37.9 mmol)in methanol (100 mL) was treated slowly with concentrated sulfuric acid(1 mL). The resulting reaction mixture was heated under reflux for 19 h.The reaction mixture was allowed to cool to 25° C. and then concentratedin vacuo to remove methanol. The resulting residue was diluted withethyl acetate (200 mL). The organic layer was washed with a saturatedaqueous sodium bicarbonate solution (3×300 mL) and a saturated aqueoussodium chloride solution (1×100 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated in vacuo to afford(4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 98%) as ayellow liquid which was used without further purification: EI-HRMS m/ecalcd for C₁₀H₁₂O₂S (M⁺) 196.0558, found 196.0559.

[0727] A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl ester(7.28 g, 37.1 mmol) in carbon tetrachloride (150 mL) was slowly treatedwith bromine (2.5 mL, 48.23 mmol). The reaction mixture was stirred at25° C. for 3 h, at which time, thin layer chromatography still indicatedthe presence of a substantial amount of starting material. The reactionmixture was treated with more bromine (2.5 mL, 48.23 mmol). The reactionmixture was stirred an additional 1 h at 25° C. and then quenched with a10% aqueous sodium bisulfite solution (200 mL). The reaction mixture wasconcentrated in vacuo to remove carbon tetrachloride. The resultingaqueous layer was extracted with ethyl acetate (3×200 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230mesh, 9/1 hexanes/ethyl acetate) afforded(3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (8.57 g, 84%)as a light yellow oil: EI-HRMS m/e calcd for C₁₀H₁₁BrO₂S (M⁺) 273.9663,found 273.9661.

[0728] A solution of diisopropylamine (4.8 mL, 34.27 mmol) in drytetrahydrofuran (30 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to−78° C. under nitrogen and then treated with a 2.5M solution ofn-butyllithium in hexanes (13.8 mL, 34.27 mmol). The resulting reactionmixture was stirred at −78° C. for 30 min and then treated dropwise witha solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester(8.57 g, 31.15 mmol) in dry tetrahydrofuran (30 mL) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). Theresulting reaction mixture was allowed to stir at −78° C. for 1 h, atwhich time, a solution of iodomethylcyclopentane (7.85 g, 37.38 mmol) ina small amount of dry tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to 25° C. where it was stirred for 15 h. Thereaction mixture was quenched with water (300 mL) and then concentratedin vacuo to remove tetrahydrofuran. The remaining aqueous phase wasextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with a saturated aqueous sodium chloride solution (1×200mL), dried over sodium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1hexanes/ethyl acetate) afforded2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methylester (9.20 g, 83%) as a light yellow oil: EI-HRMS m/e calcd forC₁₆H₂₁BrO₂S (M⁺) 356.0446, found 356.0435.

[0729] A solution of2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methylester (9.20 g, 25.75 mmol) in formic acid (30 mL) was cooled to 0° C.and then treated with a 30% aqueous hydrogen peroxide solution (15.0 mL,386.25 mmol). The resulting solution was allowed to warm to 25° C. whereit was stirred for 1.5 h. An additional amount of 30% aqueous hydrogenperoxide solution (5.0 mL, 43.00 mmol) was then added, and the reactionwas stirred at 25° C. for 3 h. The reaction was then re-cooled to 0° C.,quenched with a saturated aqueous sodium bisulfite solution, and thenextracted with ethyl acetate (2×300 mL). The combined organic layerswere then washed with a saturated aqueous sodium bicarbonate solution(2×200 mL), dried over sodium sulfate, filtered, and concentrated invacuo to afford2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (10.02 g, 100%) as a colorless gum which was used without furtherpurification: EI-HRMS m/e calcd for C₁₆H₁₉BrO₄S (M⁺) 388.0344, found388.0343.

[0730] A solution of2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methylester (10.02 g, 25.75 mol) in methanol (100 mL) and water (100 mL) wastreated with lithium hydroxide (15.4 g, 515 mmol). The reaction mixturewas stirred at 25° C. for 2 h. The reaction mixture was thenconcentrated in vacuo to remove methanol. The resulting aqueous residuewas acidified to pH=2 with a 10% aqueous hydrochloric acid solution andthen extracted with ethyl acetate (1×400 mL). The organic layer waswashed with water (1×300 mL) and a saturated aqueous sodium chloridesolution (1×300 mL). The organic layer was then dried over sodiumsulfate, filtered, and concentrated in vacuo to afford2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (9.58g, 99%) as a white solid which was used without further purification: mp149-150° C.; FAB-HRMS m/e calcd for C₁₅H₁₉BrO₄S (M+H)⁺ 375.0266, found375.0274.

[0731] A solution of2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100mg, 0.266 mmol) in methylene chloride (8 mL) was treated with dryN,N-dimethylformamide (2 drops). The reaction mixture was cooled to 0°C. and then treated dropwise with a 2M solution of oxalyl chloride inmethylene chloride (0.15 mL, 0.29 mmol). The reaction mixture wasstirred at 0° C. for 10 min and then stirred at 25° C. for 30 min. Thereaction mixture was then treated with N,N-diisopropylethylamine (0.11mL, 0.63 mmol) followed by a solution of 4-aminpyrimidine (53 mg, 0.56mmol) in dry tetrahydrofuran (3 mL). The resulting reaction mixture wasstirred at 25° C. for 17 h. The reaction mixture was concentrated invacuo. The resulting residue was adsorbed onto silica gel (Merck Silicagel 60, 230-400 mesh) and then purified via Biotage chromatography(FLASH 40S, Silica, 2/3 hexanes/ethyl acetate) to afford2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide(110 mg, 92%) as a white solid: mp 75-80° C.; EI-HRMS m/e calcd forC₁₉H₂₂BrN₃O₃S (M⁺) 451.0565, found 451.0558.

[0732] In an analogous manner, there was obtained:

[0733] a) From2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid and4-amino-2-methylpyrimidine:2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamideas a white foam: EI-HRMS m/e calcd for C₂₂H₂₃BrN₂O₃S₂(M⁺) 465.0722,found 465.0723

EXAMPLE 1492-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide

[0734]

[0735] A solution of2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 148A, 375 mg, 1.0 mmol) and triphenylphosphine(446 mg, 1.7 mmol) in methylene chloride (5 mL) was cooled to 0° C. andthen treated with N-bromosuccinimide (303 mg, 1.7 mmol) in smallportions. The reaction mixture color changed from light yellow to adarker yellow then to brown. After the complete addition of theN-bromosuccinimide, the reaction mixture was allowed to warm to 25° C.over 30 min. The brown reaction mixture was then treated with2-aminopyrazine (238 mg, 2.5 mmol). The resulting reaction mixture wasstirred at 25° C. for 19 h. The reaction mixture was then concentratedin vacuo to remove methylene chloride. Biotage chromatography (FLASH40S, Silica, 2/3 hexanes/ethyl acetate) afforded2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide(72 mg, 16%) as pink foam: EI-HRMS m/e calcd for C₁₉H₂₂BrN₃O₃S (M⁺)451.0565, found 451.0547.

EXAMPLE 1502-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-imidazol-2-yl)-propionamide

[0736]

[0737] A solution of2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 148A, 100 mg, 0.266 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(187 mg, 0.42 mmol), triethylamine (115 μL, 1.064 mmol), and2-aminoimidazole sulfate (56 mg, 0.42 mmol) in methylene chloride (10mL) was stirred at 25° C. for 15 h. The reaction mixture was partitionedbetween water and methylene chloride. The organic layer was washedsequentially with a 1N aqueous hydrochloric acid solution (1×10 mL) andwater (1×10 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M,Silica, ethyl acetate) afforded2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-imidazol-2-yl)-propionamide(69 mg, 53%) as a white solid: mp >210° C. (dec); EI-HRMS m/e calcd forC₁₈H₂₂BrN₃O₃S(M⁺) 439.0565, found 439.0566.

EXAMPLE 1512-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide

[0738]

[0739] A solution of2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 75, 125 mg, 0.389 mmol) in methylene chloride (3mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to0° C. The reaction mixture was then treated with oxalyl chloride (0.050mL, 0.583 mmol). The resulting reaction mixture was allowed to warm to25° C. where it was stirred for 1 h. The reaction mixture was thenconcentrated in vacuo. The resulting yellow gel was diluted withmethylene chloride (2 mL) and then slowly added to a solution of4-aminopyrimidine (56 mg, 0.583 mmol) and triethylamine (0.108 mL, 0.778mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixturewas stirred at 25° C. for 20 h. The reaction mixture was then dilutedwith water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), andethyl acetate (25 mL). The layers were separated, and the organic layerwas dried over magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 1/1 then 1/3 hexanes/ethylacetate) afforded2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide(34.7 mg, 22%) as a pale yellow foam: mp 79-84° C. (foam to gel);EI-HRMS m/e calcd for C₂₀H₂₂N₄O₃S (M⁺) 398.1413, found 398.1411.

EXAMPLE 1522-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0740]

[0741] A solution of2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 75, 200 mg, 0.622 mmol) in methylene chloride (5mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to0° C. The reaction mixture was then treated with oxalyl chloride (0.081mL, 0.933 mmol). The resulting reaction mixture was allowed to warm to25° C. where it was stirred for 1 h. The reaction mixture was thenconcentrated in vacuo. The resulting yellow gel was diluted withmethylene chloride (2 mL) and then slowly added to a mixture of4-amino-2-methylpyrimidine (102 mg, 0.933 mmol) and triethylamine (0.173mL, 1.24 mmol) in N,N-dimethylformamide (3 mL). The resulting reactionmixture was stirred at 25° C. for 24 h. The crude reaction mixture wasdirectly purified by Biotage chromatography (FLASH 40S, Silica, 19/1methylene chloride/methanol) to afford2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide(15 mg, 6%) as a white foam: mp 89-94° C. (foam to gel); EI-HRMS m/ecalcd for C₂₁H₂₄N₄O₃S (M⁺) 412.1569, found 412.1568.

EXAMPLE 1532-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide

[0742]

[0743] A solution of2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid(prepared as in Example 75, 200 mg, 0.622 mmol) in methylene chloride (5mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to0° C. The reaction mixture was then treated with oxalyl chloride (0.081mL, 0.933 mmol). The resulting reaction mixture was allowed to warm to25° C. where it was stirred for 1 h. The reaction mixture was thenconcentrated in vacuo. The resulting yellow gel was diluted withmethylene chloride (2 mL) and then slowly added to a mixture of2-aminopyrazine (89 mg, 0.933 mmol) and triethylamine (0.173 mL, 1.24mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixturewas stirred at 25° C. for 24 h. The reaction mixture was then dilutedwith water (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), andethyl acetate (30 mL). The layers were separated, and the organic layerwas dried over magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 19/1 methylenechloride/methanol) afforded2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamideas an impure orange foam. Re-purification by flash chromatography (MerckSilica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide(8 mg, 3%) as a yellow foam: mp 88-93° C. (foam to gel); EI-HRMS m/ecalcd for C₂₀H₂₂N₄O₃S (M⁺) 398.1413, found 398.1413.

EXAMPLE 1543-Cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide

[0744]

[0745] A solution of3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (prepared as in Example 89, 1.73 g, 5 mmol) intetrahydrofuran/water (20 mL, 3:1) was treated with lithium hydroxide(419 mg, 10 mmol). The reaction was stirred at 25° C. for 24 h. At thistime, the reaction was diluted with water (50 mL) and extracted withether (1×50 mL). The aqueous layer was acidified to pH=2 with a 2Naqueous hydrochloric acid solution. The product was extracted intomethylene chloride (3×75 mL). The combined organic layers were washedwith a saturated aqueous sodium chloride solution (3×100 mL), dried overmagnesium sulfate and sodium sulfate, filtered, and concentrated invacuo. The residue was triturated with 90/10 hexanes/ether to afford3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (1.05 g, 63.65%) as a white solid: mp 105-106° C.; EI-HRMS m/ecalcd for C₁₆H₁₉F₃O₂S (M⁺) 332.1058, found 332.1055.

[0746] A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylenechloride (10.0 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10min, the reaction mixture was treated with3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (332 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for20 min and at 25° C. for 30 min. At this time, the reaction mixture wastreated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine(0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25°C. for 20 h. The reaction mixture was then concentrated in vacuo. Flashchromatography (Merck Silica gel 60, 200-400 mesh, 90/10 hexanes/ethylacetate) afforded3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide(425 mg, 60%) as an off-white solid: mp 109-110° C; EI-HRMS m/e calcdfor C₂₁H₂₂F₃N₃O₃S (M⁺) 453.1334, found 453.1334.

[0747] In an analogous manner, there were obtained:

[0748] a) From 2-amino-5-bromopyridine and3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid:N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionamideas an off-white solid: mp 108-110C; EI-HRMS m/e calcd for C₂₁H₂₂BrF₃N₂OS(M⁺) 486.0588, found 486.0587.

[0749] b) From 2-amino-5-cyanopyridine and3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid:N-(5-Cyano-pyridin-2-yl)-3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionamideas a pale yellow oil: EI-HRMS m/e calcd for C₂₂H₂₂F₃N₃OS (M⁺) 433.1435,found 433.1429.

EXAMPLE 1553-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-oxo-2,3-dihydro-pyrimidin-4-yl)-propionamide

[0750]

[0751] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid methyl ester (prepared as in Example 89A, 2.92 g, 7.72 mmol) intetrahydrofuran/water (88 mL, 3:1) was treated with lithium hydroxide(647 mg, 15.43 mmol). The reaction was stirred at 25° C. for 3 d. Thetetrahydrofuran was then removed in vacuo. The residue was diluted withwater (50 mL) and extracted with ether (25 mL). The aqueous layer wasacidified to pH=1 with a 3N aqueous hydrochloric acid solution. Theproduct was extracted into ethyl acetate (3×75 mL) and ether (1×50 mL).The combined organic layers were washed with a saturated aqueous sodiumchloride solution (2×100 mL), dried over magnesium sulfate and sodiumsulfate, filtered, and concentrated in vacuo to give3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (2.37 g, 84.5%) as a pale-yellow semi-solid: EI-HRMS m/e calcd forC₁₆H₁₉F₃O₄S (M⁺) 364.0956, found 364.0958.

[0752] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (183 mg, 0.50 mmol) in methylene chloride (5 mL) cooled to 0° C.was treated with a 2.0M solution of oxalyl chloride in methylenechloride (0.30 mL, 0.56 mmol) and a few drops of N,N-dimethylformamide.The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for30 min. The reaction mixture was then treated with a solution ofcytosine (116.7 mg, 1.06 mmol) in tetrahydrofuran (2.0 mL) andN,N-dimethylformamide (2.0 mL) followed by N,N-diisopropylethylamine(0.20 mL, 1.20 mmol). This solution was stirred at 25° C. for 18 h. Atthis time, the reaction was concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 90/10 methylene chloride/methanol)afforded3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-oxo-2,3-dihydro-pyrimidin-4-yl)-propionamide(100 mg, 53.7%) as a white solid: mp 236-238° C.; EI-HRMS m/e calcd forC₂₀H₂₂F₃N₃O₄S (M⁺) 457.1283, found 457.1291.

[0753] In an analogous manner, there were obtained:

[0754] a) From 4-aminopyrimidine and3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid:3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamideas a pale-yellow solid: mp 85-90° C.; EI-HRMS m/e calcd forC₂₀H₂₂F₃N₃O₃S (M⁺) 441.1334, found 441.1354.

[0755] b) From 2-aminopyrazine and3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid:3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-propionamideas a white semi-solid: EI-HRMS m/e calcd for C₂₀H₂₂F₃N₃O₃S (M⁺)441.1334, found 441.1325.

[0756] c) From 4-amino-2-methylpyrimidine and3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid:3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamideas a pale-yellow oil: EI-HRMS m/e calcd for C₂₁H₂₄F₃N₃O₃S (M⁺) 455.1490,found 455.1486.

EXAMPLE 156N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide

[0757]

[0758] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (prepared as in Example 155A, 73 mg, 0.07 mmol) andtriphenylphosphine (79 mg, 0.08 mmol) in methylene chloride (5.0 mL) wascooled to 0° C. and then treated with N-bromosuccinimide (60.5 mg, 0.34mmol). The reaction mixture was stirred at 0° C. for 15 min and at 25°C. for 30 min. At this time, reaction mixture was treated with2-amino-5-bromopyridine (52 mg, 0.30 mmol) and a few drops of pyridine.The resulting reaction mixture was stirred at 25° C. for 18 h. Thereaction mixture was then diluted with methylene chloride (50 mL). Theorganic phase was washed with water (1×35 mL) and a saturated aqueoussodium chloride solution (3×35 mL), dried over magnesium sulfate andsodium sulfate, treated with charcoal, filtered through a pad of celite,and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,70-230 mesh, 70/30 hexanes/ethyl acetate) affordedN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide(128.3 mg, quant) as a white solid: mp 81-85° C.; EI-HRMS m/e calcd forC₂₁H₂₂BrF₃N₂O₃S (M⁺) 518.0486, found 518.0489.

[0759] In an analogous coupling procedure, there was obtained:

[0760] a) From 2-aminothiazole and3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (prepared as in Example 157A):3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamideas a clear oil: [α]²³ ₅₈₉=−17.21° (c=0.122, chloroform); EI-HRMS m/ecalcd for C₁₉H₂₁F₃N₂O₃S₂ (M+H+) 447.1018, found 447.1022.

EXAMPLE 1573-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamide

[0761]

[0762] A mixture of (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid(27.0 g, 121.54 mmol) and potassium carbonate (41.85 g, 302.8 mmol) intetrahydrofuran (112 mL) cooled to −10° C. was treated withtrimethylacetyl chloride (15.75 mL, 127.5 mmol). The resulting reactionmixture was stirred at −10° C. for 30 min. The reaction mixture was thentreated with a solution of (1R,2R)-(−)-pseudoephedrine (26.5 g, 160.4mmol) in tetrahydrofuran (100 mL). The resulting reaction was stirred at0° C. for 3.5 h. At this time, the reaction mixture was poured intowater (135 mL) and then extracted with ethyl acetate (3×125 mL) anddiethyl ether (1×75 mL). The combined organic layers were washed with a1N aqueous hydrochloric acid solution (1×125 mL), water (1×125 mL), asaturated aqueous sodium bicarbonate solution (3×200 mL), and asaturated aqueous sodium chloride solution (3×200 mL). The combinedorganic layers were dried over magnesium sulfate and sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (Merck Silicagel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded2-(4-fluoro-3-trifluoromethyl-phenyl)-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-acetamide(34.65 g, 77.19%) as a clear oil: EI-HRMS m/e calcd forC₁₉H₁₉F₄NO₂(M−H₂O)⁺ 351.1246, found 351.1243.

[0763] A solution of2-(4-fluoro-3-trifluoromethyl-phenyl)-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-acetamide(34.65 g, 93.81 mmol) in N,N-dimethylformamide (330 mL) was treated withsodium methanethiolate (11.14 g, 140.85 mmol). The reaction mixture wasthen heated at 100-110° C. for 24 h. At this time, the reaction waspoured onto a mixture of ice and a 1.5N aqueous hydrochloric acidsolution (150 mL). This mixture was extracted with ethyl acetate (3×150mL) and diethyl ether (1×100 mL). The combined organic layers were thenwashed with water (1×300 mL) and a saturated aqueous sodium chloridesolution (3×100 mL). The organic layer was dried over magnesium sulfateand sodium sulfate, treated with charcoal, filtered, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 33/67hexanes/ethyl acetate) affordedN-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-acetamide(24.87 g, 66.7%) as a clear oil: [α]²³ ₅₈₉=−91.35° (c=0.243,chloroform); EI-HRMS m/e calcd for C₂₀H₂₂F₃NO₂S (M−H₂O)⁺ 379.1217, found379.1218.

[0764] A solution of 1,1,1,3,3,3-hexamethyldisilazane (27.87 mL, 132.1mmol) in tetrahydrofuran (113 mL) cooled to -20° C. was treated with a2.5M solution of n-butyllithium in hexanes (47.4 mL, 118.5 mmol). Theresulting reaction mixture was stirred at −20° C. for 30 min. At thistime, the reaction mixture was treated with a solution ofN-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-acetamide(22.68 g, 57.0 mmol) in tetrahydrofuran (143 mL). The resulting solutionwas stirred at −20° C. for 30 min and then allowed to warm to 0° C. Atthis time, the reaction mixture was treated with a solution ofiodomethylcyclopentane (14.37 g, 68.4 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (14.3 mL). Theresulting reaction mixture was stirred at 0° C. for 4 h. The reactionwas then stored in the freezer overnight. At this time, the reactionmixture was poured into a saturated aqueous sodium chloride solution(250 mL) and ethyl acetate (250 mL). The organic layer was separated.The aqueous phase was back-extracted with ethyl acetate (2×125 mL) andether (1×100 mL). The combined organic layers were washed with a 1Naqueous hydrochloric acid solution (1×150 mL), water (1×150 mL), asaturated aqueous sodium bicarbonate solution (2×200 mL), a saturatedaqueous sodium chloride solution (3×250 mL), and a saturated aqueouslithium chloride solution (1×150 mL). The organic layer was then driedover magnesium sulfate and sodium sulfate, treated with charcoal,filtered, and concentrated in vacuo. The crude material wasrecrystallized from ethyl acetate to afford3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2(R)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionamide(21.07 g, 77.1%) as a white solid: mp 145-146° C.; [α]²³ ₅₈₉=−80.54°(c=0.149, chloroform); FAB-HRMS m/e calcd for C₂₆H₃₂F₃NO₂S (M−H₂O)⁺461.2000, found 461.1995.

[0765] A solution of3-cyclopentyl-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl-2(R)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionamide(21.01 g, 43.8 mmol) in dioxane (105 mL) was treated with an 18N aqueoussulfuric acid solution (35 mL). The resulting reaction mixture was thenheated at 115° C. for 16 h. The reaction mixture was then cooled to 25°C., poured onto ice water (500 mL), and extracted with ethyl acetate(3×250 mL) and ether (1×125 mL). The combined organic layers were washedwith water (1×500 mL) and a saturated aqueous sodium chloride solution(3×500 mL), dried over magnesium sulfate and sodium sulfate, treatedwith charcoal, filtered through a pad of celite, and concentrated invacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20hexanes/ethyl acetate) afforded3-cyclopentyl-2(R)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (12.14 g, 83.4%) as a pale-yellow solid: mp 78-80° C.; [α]²³₅₈₉=−46.49° (c=0.185, chloroform); EI-HRMS m/e calcd for C₁₆H₁₉F₃O₂S(M)⁺ 332.1058, found 332.1068.

[0766] A slurry of3-cyclopentyl-2(R)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionicacid (6.65 g, 20.0 mmol) in formic acid (3.8 mL) cooled to 0° C. wastreated with a 30% aqueous hydrogen peroxide solution (11.4 mL). Theresulting solution was stirred at 0° C. for 15 min and at 25° C. for 18h. At this time, the reaction was treated with tetrahydrofuran (5 mL),cooled to 0° C., and then treated with an additional amount of 30%aqueous hydrogen peroxide solution (11.4 mL). The reaction was thenstirred at 25° C. for 4 h. At this time, the reaction was poured onto aslurry of ice water (125 mL) and then extracted into methylene chloride(3×125 mL). The combined organic layers were washed with a saturatedaqueous sodium chloride solution (3×25 mL), dried over sodium sulfateand magnesium sulfate, filtered, and concentrated in vacuo. The residuewas then retreated under the same reaction conditions and work upprocedure to complete the conversion of the sulfoxide to the desiredsulfone. Biotage chromatography (FLASH 40M, Silica, 100% ethyl acetate)afforded3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (7.29 g, quant.) as a white solid: mp 100-102° C.; [α]²³₅₈₉=−27.63° (c=0.351, chloroform); FAB-HRMS m/e calcd for C₁₆H₁₉F₃O₄S(M)⁺ 364.0956, found 364.0954.

[0767] A solution of3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (8.32 g, 20.0 mmol) in methylene chloride (100 mL) cooled to 0° C.was treated with a 2.0M solution of oxalyl chloride in methylenechloride (11.14 mL, 22.28 mmol) and N,N-dimethylformamide (0.5 mL). Thereaction mixture was stirred at 0° C. for 45 min and at 25° C. for 1 h.The reaction mixture was then cooled to 0° C. and treated with asolution of 4-aminopyrimidine (4.02 g, 4.28 mmol) in tetrahydrofuran (60mL) followed by pyridine (6.0 mL, 74.2 mmol). This solution was stirredat 0° C. for 15 min and at 25° C. for 16 h. At this time, the reactionwas poured onto a slurry of ice water (100 g) and then extracted withethyl acetate (3×250 mL) and ether (1×200 mL). The combined organiclayers were washed with water (1×500 mL) and a saturated aqueous sodiumchloride solution (3×300 mL). The organic layer was then dried oversodium sulfate and magnesium sulfate, treated with charcoal, filteredthrough a pad of celite, and concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate)afforded3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamide(6.36 g, 72.1%) as a white solid: mp 85-90° C.; [α]²³ ₅₈₉=−32.53°(c=0.166, chloroform); EI-HRMS m/e calcd for C₂₀H₂₂F₃N₃O₃S (M⁺)441.1334, found 441.1333.

[0768] In an analogous manner, there were obtained:

[0769] a) From 2-aminopyrazine and3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid:3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-propionamideas an off-white solid: mp 78-80° C.; [α]²³ ₅₈₉=−27.32° (c=0.183,chloroform); EI-HRMS m/e calcd for C₂₀H₂₂F₃N₃O₃S (M⁺) 441.1334, found441.1342.

[0770] b) From4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-2-methyl-pyrimidine (preparedas in Example 144) and3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid:3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamideas a pale-yellow oil: [α]²³ ₅₈₉=−12.45° (c=0.273, chloroform); EI-HRMSm/e calcd for C₂₁H₂₄F₃N₃O₃S (M⁺) 455.1490, found 455.1499.

EXAMPLE 1583-Cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrimidin-4-yl-propionamide

[0771]

[0772] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid(prepared as in Example 14, 150 mg, 0.439 mmol), triethylamine (0.184mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (291 mg, 0.659 mmol), and 4-aminopyrimidine (63 mg,0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C.overnight. The crude reaction mixture was directly purified by Biotagechromatography (FLASH 40M, Silica, 1/2 hexanes/ethyl acetate) to afford3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrimidin-4-yl-propionamide(56 mg, 30%) as a pale yellow foam: mp 91-95° C. (foam to gel); EI-HRMSm/e calcd for C₁₉H₂₂N₄O₅S (M⁺) 418.1311, found 418.1310.

EXAMPLE 1593-Cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide

[0773]

[0774] A mixture of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid(prepared as in Example 14, 250 mg, 0.732 mmol), triethylamine (0.306mL, 2.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (487 mg, 1.10 mmol), and 4-amino-2-methylpyrimidine(120 mg, 1.10 mmol) in methylene chloride (5 mL) was stirred at 25° C.for 24 h. The reaction mixture was then diluted with water (25 mL), a 1Naqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL).The layers were separated, and the organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo. Biotagechromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) affordedimpure3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide.Re-purification by flash chromatography (Merck Silica gel 60, 230-400mesh, 1/1 then 1/3 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide(59 mg, 18%) as a white foam: mp 96-99° C. (foam to gel); EI-HRMS m/ecalcd for C₂₀H₂₄N₄O₅S (M⁺) 432.1467, found 432.1470.

EXAMPLE 1603-Cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide

[0775]

[0776] A solution of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid(prepared as in Example 14, 150 mg, 0.439 mmol) in methylene chloride (2mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to0° C. The reaction mixture was then treated with oxalyl chloride (0.042mL, 0.483 mmol). The resulting reaction mixture was allowed to warm to25° C. where it was stirred for 30 min. The reaction mixture was thentreated with a mixture of cytosine (102 mg, 0.922 mmol) andN,N-diisopropylethylamine (0.191 mL, 1.098 mmol) inN,N-dimethylformamide (2 mL). The resulting reaction mixture was allowedto stir at 25° C. overnight. The reaction mixture was then diluted withwater (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethylacetate (30 mL). The layers were separated, and the organic layer wasdried over magnesium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 20/1 methylenechloride/methanol) afforded impure3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide(25 mg) as a pale yellow solid. Re-purification by recrystallizationfrom chloroform afforded3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide(12 mg, 6.5%) as a white solid: mp 256-258° C. (dec); FAB-HRMS m/e calcdfor C₁₉H₂₂N₄O₆S (M+H)⁺ 435.1338, found 435.1334.

EXAMPLE 1613-Cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrazin-2-yl-propionamide

[0777]

[0778] A mixture of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid(prepared as in Example 14, 250 mg, 0.732 mmol), triethylamine (0.306mL, 2.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (487 mg, 1.10 mmol), and 2-aminopyrazine (105 mg,1.10 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 18 h.The reaction mixture was then diluted with water (25 mL), a 1N aqueoushydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layerswere separated, and the organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S,Silica, 19/1 methylene chloride/methanol) afforded impure3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrazin-2-yl-propionamideas a white foam. This white foam was dissolved in ethyl acetate (2 mL)and then added to hexanes (50 mL). A white precipitate formed, and thesolid was collected by filtration to afford3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrazin-2-yl-propionamide(23.3 mg, 7.6%) as a white solid: mp 104-108° C. (gel formation);EI-HRMS m/e calcd for C₁₉H₂₂N₄O₅S (M⁺) 418.1311, found 418.1309.

EXAMPLE 1623-Cyclopentyl-N-(1H-imidazol-2-yl)-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide

[0779]

[0780] A mixture of3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid(prepared as in Example 14, 150 mg, 0.439 mmol), triethylamine (0.184mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (291 mg, 0.659 mmol), and 2-aminoimidazole sulfate(87 mg, 0.659 mmol) in methylene chloride (4 mL) andN,N-dimethylformamide (1.5 mL) was stirred at 25° C. for 48 h. Thereaction mixture was then diluted with water (25 mL), a 1N aqueoushydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layerswere separated, and the organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo to afford a yellow gel. This yellowgel was diluted with methylene chloride (5 mL), and an off-white solidprecipitated. The off-white solid was collected by filtration, and thentreated with acetone (5 mL). The acetone mixture was heated to a boil,allowed to cool, and then filtered to afford3-cyclopentyl-N-(1H-imidazol-2-yl)-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide(25 mg, 14%) as a white solid: mp 243-244° C.; EI-HRMS m/e calcd forC₁₈H₂₂N₄O₅S (M⁺) 406.1311, found 406.1311.

EXAMPLE 1633-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide

[0781]

[0782] A solution of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionicacid (prepared as in Example 54A, 200 mg, 0.70 mmol) in methylenechloride (5 mL) was cooled to 0° C. and then treated with a 2M solutionof oxalyl chloride in methylene chloride (0.52 mL, 1.0 mmol) andN,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0°C. for 30 min and then treated with a solution of 2-aminopyrazine (133mg, 1.4 mmol) in tetrahydrofuran (10 mL) followed by pyridine (0.28 ml,3.5 mmol). The resulting reaction mixture was stirred at 25° C. for 16h. The reaction mixture was then diluted with water (10 mL) andextracted with methylene chloride (3×15 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo.Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate)afforded3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide(192 mg, 76%) as a colorless oil: [α]²³ ₅₈₉=−62.1° (c=0.095,chloroform); EI-HRMS m/e calcd for C₁₈H₁₉N₃OCl (M⁺) 363.0905, found363.0893.

EXAMPLE 164N-(5-Brom-pyridin-2-yl)-2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide

[0783]

[0784] A solution of triphenylphosphine (241 mg, 0.92 mmol) in methylenechloride (3 mL) was cooled to 0° C. and then slowly treated withN-bromosuccinimide (164 mg, 0.92 mmol). The reaction mixture was stirredat 0° C. for 10 min and then treated with2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (prepared as inExample 64, 250 mg, 0.84 mmol). The resulting reaction mixture wasstirred at 0° C. for 5 min and then allowed to warm to 25° C. where itwas stirred for 30 min. The reaction mixture was then treated with2-amino-5-bromopyridine (320 mg, 1.85 mmol). The crude reaction mixturewas then directly purified by flash chromatography (Merck Silica gel 60,230-400 mesh, 3/1 hexanes/ethyl acetate) to affordN-(5-bromo-pyridin-2-yl)-2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide(216 mg, 57%) as a pale yellow solid: mp 128-130° C.; EI-HRMS m/e calcdfor C₁₉H₁₉BrClN₃O₃ (M⁺) 451.0298, found 451.0300.

EXAMPLE 1653-Cyclopentyl-N-pyrimidin-4-yl-2-(3-trifluoromethyl-phenyl)-propionamide

[0785]

[0786] A solution of3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared asin Example 88, 152 mg, 0.532 mmol) in methylene chloride (10 mL) wastreated with dry N,N-dimethylformamide (3 drops). The reaction mixturewas cooled to 0° C. and then treated dropwise with a 2M solution ofoxalyl chloride in methylene chloride (0.30 mL, 0.58 mmol). The reactionmixture was stirred at 0° C. for 10 min and then stirred at 25° C. for30 min. The reaction mixture was then treated withN,N-diisopropylethylamine (0.22 mL, 1.26 mmol) followed by a solution of4-aminopyrimidine (106 mg, 1.12 mmol) in dry tetrahydrofuran (5 mL). Theresulting reaction mixture was stirred at 25° C. for 17 h. The reactionmixture was concentrated in vacuo. The resulting residue was adsorbedonto silica gel (Merck Silica gel 60, 230-400 mesh) and then purifiedvia Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethylacetate) to afford3-cyclopentyl-N-pyrimidin-4-yl-2-(3-trifluoromethyl-phenyl)-propionamide(170 mg, 88%) as a white solid: mp 113-115° C.; EI-HRMS m/e calcd forC₁₉H₂₀F₃N₃O (M⁺) 363.1558, found 363.1553.

[0787] In an analogous manner, there were obtained:

[0788] a) From 3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acidand 4-amino-2-methylpyrimidine:3-Cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-2-(3-trifluoromethyl-phenyl)-propionamideas a colorless gum: EI-HRMS m/e calcd for C₂₀H₂₂F₃N₃O (M⁺) 377.1715,found 377.1715.

[0789] b) From 3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acidand 2-aminopyrazine:3-Cyclopentyl-N-pyrazin-2-yl-2-(3-trifluoromethyl-phenyl)-propionamideas a pale yellow gum: EI-HRMS m/e calcd for C₂₉H₂₀F₃N₃O (M⁺) 363.1558,found 363.1558.

EXAMPLE 166{2-[3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticAcid Ethyl Ester

[0790]

[0791] A solution of3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid(prepared as in Example 87, 250 mg, 0.82 mmol) in methylene chloride(8.22 mL) cooled to 0° C. was treated with a 2.0M solution of oxalylchloride in methylene chloride (0.45 mL, 0.90 mmol) and a few drops ofN,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10min and at 25° C. for 20 min. The reaction mixture was then treated witha solution of (2-amino-thiazol-4-yl)-acetic acid ethyl ester (337 mg,1.81 mmol) in tetrahydrofuran (4.11 mL) and N,N-diisopropylethylamine(0.34 mL, 1.97 mmol). This solution was stirred at 25° C. for 18 h. Atthis time, the reaction was concentrated in vacuo. Flash chromatography(Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate)afforded{2-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester (208.7 mg, 53.7%) as a pale-yellow gum: EI-HRMS m/ecalcd for C₂₁H₂₂F₄N₂O₃S (M⁺) 472.1444, found 472.1442.

EXAMPLE 1673-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide

[0792]

[0793] A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylenechloride (10.0 mL) was cooled to 0° C. and then treated withN-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10min, the reaction mixture was treated with3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid(prepared as in Example 87, 304 mg, 1.0 mmol). The reaction mixture wasstirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, thereaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixturewas stirred at 25° C. for 20 h. The reaction mixture was thenconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,200-400 mesh, 90/10 hexanes/ethyl acetate) afforded3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide(425 mg, 60%) as a white solid: mp 121-122° C.; EI-HRMS m/e calcd forC₂₀H₁₉F₄N₃O₃ (M⁺) 425.1363, found 425.1363.

[0794] In an analogous manner, there was obtained:

[0795] a) From 2-amino-5-cyanopyridine and3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid:N-(5-Cyano-pyridin-2-yl)-3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamideas a pale-yellow oil: EI-HRMS m/e calcd for C₂₁H₁₉F₄N₃O (M⁺) 405.1464,found 445.1477.

EXAMPLE 1686-[3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propinylamino]-nictinicAcid Methyl Ester

[0796]

[0797] A solution of3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid(prepared as in Example 87, 202 mg, 0.66 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(294 mg, 0.66 mmol), and 6-amino-nicotinic acid methyl ester (111 mg,0.73 mmol) in N,N-dimethylformamide (3.32 mL) at 25° C. was treated withN,N-diisopropylethylamine (0.24 mL, 1.39 mmol). The reaction mixture wasstirred at 25° C. for 12 h. At this time, the reaction was poured intowater (50 mL) and extracted into ethyl acetate (3×35 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 80/20 hexanes/ethyl acetate) afforded6-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-nicotinicacid methyl ester (36.7 mg, 12.6%) as a white foam: EI-HRMS m/e calcdfor C₂₂H₂₂F₄N₂O₃ (M⁺) 438.1566, found 438.1568.

[0798] In an analogous coupling procedure, there were obtained:

[0799] a) From 2-amino-5-bromopyridine and3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid:N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamideas a pale-yellow oil: EI-HRMS m/e calcd for C₂₀H₁₉BrF₄N₂O (M⁺) 458.0617,found 458.0612.

[0800] b) From 2-aminoimidazole sulfate and3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionicacid (prepared as in Example 155A):3-Cyclopentyl-N-(1H-imidazol-2-yl)-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamideas a white solid: mp 270-275° C.; EI-HRMS m/e calcd for C₁₉H₂₂F₃N₃O₃S(M⁺) 429.1334, found 429.1331.

Biological Activity Examples Example A

[0801] In Vitro Glucokinase Activity

[0802] Glucokinase Assay: Glucokinase (GK) was assayed by coupling theproduction of glucose-6-phosphate to the generation of NADH withglucose-6-phosphate dehydrogenase (G6PDH, 0.75-1 kunits/mg; BoehringerMannheim, Indianapolis, Ind.) from Leuconostoc mesenteroides as thecoupling enzyme (Scheme 2). Recombinant

[0803] Human liver GK1 was expressed in E. coli as a glutathioneS-transferase fusion protein (GST-GK) [Liang et al, 1995] and waspurified by chromatography over a glutathione-Sepharose 4B affinitycolumn using the procedure provided by the manufacturer (AmershamPharmacia Biotech, Piscataway, N.J.). Previous studies have demonstratedthat the enzymatic properties of native GK and GST-GK are essentiallyidentical (Liang et al, 1995; Neet et al., 1990).

[0804] The assay was conducted at 25° C. in a flat bottom 96-well tissueculture plate from Costar (Cambridge, Mass.) with a final incubationvolume of 120 μl. The incubation mixture contained: 25 mM Hepes buffer(pH, 7.1), 25 mM KCl, 5 mM D-glucose, 1 mM ATP, 1.8 mM NAD, 2 mM MgCl₂,1 μM sorbitol-6-phosphate, 1 mM dithiothreitol, test drug or 10% DMSO,1.8 unit/ml G6PDH, and GK (see below). All organic reagents were >98 %pure and were from Boehringer Mannheim with the exceptions of D-glucoseand Hepes that were from Sigma Chemical Co, St Louis, Mo. Test compoundswere dissolved in DMSO and were added to the incubation mixture minusGST-GK in a volume of 12 μl to yield a final DMSO concentration of 10%.This mix was preincubated in the temperature controlled chamber of aSPECTRAmax 250 microplate spectrophotometer (Molecular DevicesCorporation, Sunnyvale, Calif.) for 10 minutes to allow temperatureequilibrium and then the reaction was started by the addition of 20 μlGST-GK.

[0805] After addition of enzyme, the increase in optical density (OD) at340 nm was monitored over a 10 minute incubation period as a measure ofGK activity. Sufficient GST-GK was added to produce an increase in OD₃₄₀of 0.08 to 0.1 units over the 10 minute incubation period in wellscontaining 10% DMSO, but no test compound. Preliminary experimentsestablished that the GK reaction was linear over this period of timeeven in the presence of activators that produced a 5-fold increase in GKactivity. The GK activity in control wells was compared with theactivity in wells containing test GK activators, and the concentrationof activator that produced a 50% increase in the activity of GK, i.e.,the SC_(1.5), was calculated. All of the compounds of formula Idescribed in the Synthesis Examples had an SC_(1.5) less than or equalto 30 μM.

References for Example A

[0806] Liang, Y., Kesavan, P., Wang, L., Niswender, K., Tanizawa, Y.,Permut, M. A., Magnuson, M., and Matschinsky, F. M. Variable effects ofmaturity-onset-diabetes-of-youth (MODY)-associated glucokinase mutationson the substrate interactions and stability of the enzyme. Biochem. J.309: 167-173, 1995.

[0807] Neet, K., Keenan, R. P., and Tippett, P. S. Observation of akinetic slow transition in monomeric glucokinase. Biochemistry29;770-777, 1990.

Example B

[0808] In Vivo Activity

[0809] Glucokinase Activator in vivo Screen Protocol: C57BL/6J mice areorally dosed via gavage with Glucokinase (GK) activator at 50 mg/kg bodyweight following a two hour fasting period. Blood glucose determinationsare made five times during the six hour post-dose study period.

[0810] Mice (n=6) are weighed and fasted for a two hour period prior tooral treatment. GK activators are formulated at 6.76 mg/ml in Gelucirevehicle (Ethanol:Gelucire44/14:PEG400q.s. 4:66:30 v/w/v. Mice are dosedorally with 7.5 μl formulation per gram of body weight to equal a 50mg/kg dose. Immediately prior to dosing, a pre dose (time zero) bloodglucose reading is acquired by snipping off a small portion of theanimals tail (˜1 mm) and collecting 15 μl blood into a heparinizedcapillary tube for analysis. Following GK activator administration,additional blood glucose readings are taken at 1, 2, 4 and 6 hours postdose from the same tail wound. Results are interpreted by comparing themean blood glucose values of six vehicle treated mice with six GKactivator treated mice over the six hour study duration. Compounds areconsidered active when they exhibit a statistically significant (p≦0.05)decrease in blood glucose compared to vehicle for two consecutive assaytime points.

What is claimed is:
 1. A compound comprising an amide of the formula:

wherein, the * indicates an asymmetric carbon atom, R¹ and R² areindependently hydrogen, halo, amino, hydroxyamino, cyano, nitro, loweralkyl, —OR⁵, —C(O)OR⁶, perfluoro-lower alkyl, lower alkyl thio,perfluoro-lower alkyl thio, lower alkyl sulfonyl, lower alkoxy loweralkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, orsulfonamido; R³ is cycloalkyl having from 3 to 7 carbon atoms or loweralkyl having from 2 to 4 carbon atoms; R⁴ is an unsubstituted ormono-substituted five- or six-membered heteroaromatic ring connected bya ring carbon atom to the amide group shown, which five- or six-memberedheteroaromatic ring contains from 1 to 3 heteroatoms selected fromsulfur, oxygen or nitrogen, with one heteroatom being nitrogen which isadjacent to the connecting ring carbon atom; said mono-substitutedheteroaromatic ring being monosubstituted at a position on a ring carbonatom other than adjacent to said connecting carbon atom with asubstituent selected from the group consisting of lower alkyl, halo,nitro, cyano, perfluoro-lower alkyl, oxo, —(CH₂)_(n)—OR⁷,—(CH₂)_(n)—C(O)—OR⁷, —(CH₂)_(n)—C(O)—NH—R⁷, —C(O)C(O)—OR⁷, or—(CH₂)_(n)—NHR⁷; n is 0, 1, 2, 3 or 4; R⁵ is hydrogen, lower alkyl, orperfluoro-lower alkyl; R⁶ is lower alkyl; and R⁷ is hydrogen or loweralkyl; or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, wherein the amide is the R configuration at the asymmetriccarbon shown.
 3. The compound of claim 1, wherein R³ is cycloalkylhaving from 3 to 7 carbon atoms.
 4. The compound of claim 3, wherein R³is cyclopentyl.
 5. The compound of claim 4, wherein R⁴ is unsubstitutedthiazole.
 6. The compound of claim 5, wherein one of R¹ and R² ishydrogen, halo, perfluoro-lower alkyl and the other of said R¹ and R² ishalo, nitro or perfluoro-lower alkyl.
 7. The compound of claim 6,wherein said amide is2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
 8. Thecompound of claim 6, wherein said amide is2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
 9. Thecompound of claim 6, wherein said amide is2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
 10. Thecompound of claim 6, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide. 11.The compound of claim 6, wherein said amide is3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide.12. The compound of claim 6, wherein said amide is3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide.13. The compound of claim 6, wherein said amide is3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide.14. The compound of claim 6, wherein said amide is3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide.15. The compound of claim 6, wherein said amide is3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-thiazol-2-yl-propionamide.16. The compound of claim 5, wherein one of R¹ and R² is amino, nitro,halo or hydrogen and the other of said R¹ and R² is amino, cyano ornitro.
 17. The compound of claim 16, wherein said amide is3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-yl-propionamide.
 18. Thecompound of claim 16, wherein said amide is2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
 19. Thecompound of claim 16, wherein said amide is2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
 20. Thecompound of claim 16, wherein said amide is2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.21. The compound of claim 16, wherein said amide is2-(4-cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
 22. Thecompound of claim 16, wherein said amide is3-cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-yl-propionamide.
 23. Thecompound of claim 5, wherein one of R¹ and R² is lower alkylthio,perfluoro-lower alkyl thio, halo or hydrogen and the other isperfluoro-lower alkylthio, lower alkylsulfinyl or lower alkylthio. 24.The compound of claim 23, wherein said amide is3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide.25. The compound of claim 23, wherein said amide is3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide.26. The compound of claim 23, wherein said amide is3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide.27. The compound of claim 23, wherein said amide is3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide.28. The compound of claim 5, wherein one of R¹ and R² is lower alkylsulfonyl, hydrogen, nitro, amino, cyano, hydroxylamino, sulfonamido orhalo, and the other of said R¹ and R² is lower alkyl sulfonyl.
 29. Thecompound of claim 28, wherein said amide is3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide.30. The compound of claim 28, wherein said amide is3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide.31. The compound of claim 28, wherein said amide is2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.32. The compound of claim 28, wherein said amide is3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide.33. The compound of claim 28, wherein said amide is2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.34. The compound of claim 28, wherein said amide is3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide.35. The compound of claim 28, wherein said amide is2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.36. The compound of claim 28, wherein said amide is3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide. 37.The compound of claim 28, wherein said amide is2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide.38. The compound of claim 28, wherein said amide is3-cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-N-thiazol-2-yl-propionamide.39. The compound of claim 28, wherein said amide is(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide.40. The compound of claim 5, wherein one of R¹ and R² is lower alkylsulfonyl, and the other is halo or perfluoro-lower alkyl.
 41. Thecompound of claim 40, wherein said amide is3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide.42. The compound of claim 40, wherein said amide is3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide43. The compound of claim 40, wherein said amide is3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide.44. The compound of claim 40, wherein said amide is2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.45. The compound of claim 40, wherein said amide is2-[3-chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide.46. The compound of claim 40, wherein said amide is2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.47. The compound of claim 5, wherein one of R¹ and R² is perfluoro-loweralkyl sulfonyl or hydrogen and the other is perfluoro-lower alkylsulfonyl.
 48. The compound of claim 47, wherein said amide is3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide.49. The compound of claim 47, wherein said amide is3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propionamide.50. The compound of claim 5, wherein one of R¹ and R² is —OR⁵, or—C(O)—OR⁶ and the other of said R¹ and R² is hydrogen or —OR⁵; and R⁵and R⁶ are as above.
 51. The compound of claim 50, wherein said amide is3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide.52. The compound of claim 50, wherein said amide is3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide.
 53. Thecompound of claim 50, wherein said amide is3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide.
 54. Thecompound of claim 50, wherein said amide is3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide. 55.The compound of claim 50, wherein said amide is3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide. 56.The compound of claim 50, wherein said amide is3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide.
 57. Thecompound of claim 50, wherein said amide is3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide.
 58. Thecompound of claim 50, wherein said amide is4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid methylester.
 59. The compound of claim 5, wherein one of R¹ and R² is —OR⁵ andthe other is halo.
 60. The compound of claim 59, wherein said amide is3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide.61. The compound of claim 59, wherein said amide is3-cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide.62. The compound of claim 5, wherein one of R¹ and R² is hydrogen andthe other is lower alkoxy lower alkyl sulfonyl.
 63. The compound ofclaim 62, wherein said amide is3-cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide64. The compound of claim 4 wherein R⁴ is a mono-substituted thiazolewith said substituent.
 65. The compound of claim 64, wherein saidsubstituent is —(CH₂)_(n)—OR⁷ and n and R⁷ are as above.
 66. Thecompound of claim 65, wherein one of R¹ and R² is halo and the other ofsaid R¹ and R² is hydrogen or halo.
 67. The compound of claim 66,wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide.68. The compound of claim 66, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-propionamide.69. The compound of claim 66, wherein said amide is2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide.70. The compound of claim 66, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide.71. The compound of claim 65, wherein one of R¹ and R² is lower alkylsulfonyl, and the other of said R¹ and R² is lower alkyl sulfonyl orhydrogen.
 72. The compound of claim 71 ,wherein said amide is3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide.73. The compound of claim 71 ,wherein said amide is3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide.74. The compound of claim 64, wherein said substituent is lower alkyl.75. The compound of claim 74 wherein one of R¹ and R² is hydrogen orhalo and the other of said R¹ and R² is halo.
 76. The compound of claim75, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methyl-thiazol-2-yl)-propionamide.77. The compound of claim 75, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-thiazol-2-yl)-propionamide.78. The compound of claim 74 wherein one of R¹ and R² is lower alkylsulfonyl and the other is hydrogen or halo.
 79. The compound of claim78, wherein said amide is3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(4-methyl-thiazol-2-yl)-propionamide.80. The compound of claim 78, wherein said amide is3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methyl-thiazol-2-yl)-propionamide.81. The compound of claim 78, wherein said amide is2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-thiazol-2-yl)-propionamide.82. The compound of claim 78, wherein said amide is2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(4-methyl-thiazol-2-yl)-propionamide.83. The compound of claim 64, wherein said substituent is—(CH₂)_(n)—C(O)—OR⁷ wherein n is 0 or 1 and R⁷ is hydrogen, or loweralkyl.
 84. The compound of claim 83, wherein one of R¹ and R² ishydrogen and the other is halo.
 85. The compound of claim 84, whereinsaid amide is{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester.
 86. The compound of claim 84, wherein said amide is{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester.
 87. The compound of claim 84, wherein said amide is2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 88. The compound of claim 84, wherein said amide is2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid ethyl ester.
 89. The compound of claim 84, wherein said amide is{2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester.
 90. The compound of claim 84, wherein said amide is2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 91. The compound of claim 84, wherein said amide is2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid ethyl ester.
 92. The compound of claim 84, wherein said amide is{2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester.
 93. The compound of claim 83, wherein one of R¹ or R²is halo and the other is perfluoro-lower alkyl.
 94. The compound ofclaim 93 wherein said amide is{2-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester.
 95. The compound of claim 83, wherein R¹ and R² areeach independently halo.
 96. The compound of claim 95, wherein saidamide is{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid.
 97. The compound of claim 95, wherein said amide is{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester.
 98. The compound of claim 95, wherein said amide is2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid.
 99. The compound of claim 95, wherein said amide is2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid.
 100. The compound of claim 95, wherein said amide is{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester.
 101. The compound of claim 95, wherein saidamide is(2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 102. The compound of claim 95, wherein said amide is2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid methyl ester.
 103. The compound of claim 95, wherein said amide is2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylicacid ethyl ester.
 104. The compound of claim 95, wherein said amide is2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester.
 105. The compound of claim 95, wherein said amide is2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 106. The compound of claim 83, wherein one of R¹ orR² is nitro, amino or hydrogen and the other of said R¹ and R² is nitroor amino.
 107. The compound of claim 106, wherein said amide is{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester.
 108. The compound of claim 106, wherein said amide is{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester.
 109. The compound of claim 106, wherein said amide is2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 110. The compound of claim 106, wherein said amide is2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester.
 111. The compound of claim 106, wherein said amide is{2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceticacid methyl ester.
 112. The compound of claim 106, wherein said amide is2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 113. The compound of claim 83, wherein one of R¹ andR² is lower alkyl sulfonyl, perfluoro-lower alkyl, halo or hydrogen andthe other of said R¹ and R² is lower alkyl sulfonyl.
 114. The compoundof claim 113, wherein said amide is(2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester.
 115. The compound of claim 113, wherein said amide is(2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 116. The compound of claim 113, wherein said amide is{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid ethyl ester.
 117. The compound of claim 113, wherein said amide is{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-4-aceticacid methyl ester.
 118. The compound of claim 113, wherein said amide is{2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-aceticacid methyl ester.
 119. The compound of claim 113, wherein said amide is2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 120. The compound of claim 83, wherein one of R1 andR2 is perfluoro-lower alkyl sulfonyl and the other is hydrogen, halo, orperfluoro-lower alkyl.
 121. The compound of claim 120, wherein saidamide is2-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid methyl ester.
 122. The compound of claim 120, wherein said amide is2-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylicacid ethyl ester.
 123. The compound of claim 120, wherein said amide is2-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazole-4-aceticacid methyl ester.
 124. The compound of claim 120, wherein said amide is{2-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazole-4-yl}-aceticacid ethyl ester.
 125. The compound of claim 64, wherein saidsubstituent is —C(O)—C(O)—OR⁷ wherein R⁷ is as above.
 126. The compoundof claim 125, wherein one of R¹ and R² are hydrogen and the other ofsaid R¹ and R² is nitro or amino.
 127. The compound of claim 126,wherein said amide is{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester.
 128. The compound of claim 125, wherein one of R¹ andR² is halo or perfluoro-lower alkyl and the other of said R¹ and R² isperfluoro-lower alkyl, halo or hydrogen.
 129. The compound of claim 128,wherein said amide is{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]thiazol-5-yl}-oxo-aceticethyl ester.
 130. The compound of claim 128, wherein said amide is{2-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester.
 131. The compound of claim 128, wherein said amide is{2-[3-cyclopentyl2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-oxo-acetic acidethyl ester.
 132. The compound of claim 128, wherein said amide is(2R)-{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-5-yl}-oxo-aceticacid ethyl ester.
 133. The compound of claim 128, wherein said amide is(2R)-{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester.
 134. The compound of claim 125, wherein said one of R¹and R² is hydrogen or halo and the other of said R¹ and R² is loweralkyl sulfonyl.
 135. The compound of claim 134, wherein said compound is{2-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-oxo-aceticacid ethyl ester.
 136. The compound of claim 64, wherein saidsubstitutent is nitro.
 137. The compound of claim 136 wherein R¹ and R²are each independently halo.
 138. The compound of claim 136, whereinsaid amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro-thiazol-2-yl)-propionamide.139. The compound of claim 64, wherein said substituent is—(CH₂)_(n)—C(O)—NH—R⁷ and n and R⁷ are as in claim
 1. 140. The compoundof claim 139 wherein one of R¹ and R² is halo or lower alkyl sulfonyland the other is halo or hydrogen.
 141. The compound of claim 140,wherein said amide is2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylicacid amide.
 142. The compound of claim 140, wherein said amide is2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylicacid amide.
 143. The compound of claim 64, wherein said substituent ishalo.
 144. The compound of claim 143, wherein one of R¹ and R² is haloor hydrogen and the other is lower alkyl sulfonyl.
 145. The compound ofclaim 144, wherein said amide isN-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide.146. The compound of claim 144, wherein said amide isN-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide.147. The compound of claim 144, wherein said amide isN-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide.148. The compound of claim 144, wherein said amide isN-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide.149. The compound of claim 144, wherein said amide isN-(5-bromo-thiazol-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide.150. The compound of claim 4 wherein R⁴ is unsubstituted pyridine. 151.The compound of claim 150, wherein one of R¹ and R² is halo and theother is lower alkyl sulfonyl.
 152. The compound of claim 151, whereinsaid amide is3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide.153. The compound of claim 150, wherein one of R¹ and R² is halo,perfluoro-lower alkyl or hydrogen and the other of said R¹ and R² ishalo, perfluoro-lower alkyl, amino, cyano or nitro.
 154. The compound ofclaim 153, wherein said amide is3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide.155. The compound of claim 153, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide. 156.The compound of claim 153, wherein said amide is3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-2-propionamide.157. The compound of claim 153, wherein said amide is2-(3-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
 158. Thecompound of claim 153, wherein said amide is2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
 159. Thecompound of claim 153, wherein said amide is2-(4-cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
 160. Thecompound of claim 153, wherein said amide is2-(4-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
 161. Thecompound of claim 153, wherein said amide is2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.162. The compound of claim 153, wherein said amide is3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide.
 163. Thecompound of claim 153, wherein said amide is3-cyclopentyl-2-(R)-(3,4-dichlorophenyl)-N-pyridin-2-yl-propionamide.164. The compound of claim 153, wherein said amide is3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide.165. The compound of claim 150, wherein one of R¹ and R² is lower alkylthio, perfluoro-lower alkyl thio or cyano, and the other is hydrogen.166. The compound of claim 165, wherein said amide is3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide.167. The compound of claim 165, wherein said amide is3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide.168. The compound of claim 150, wherein one of R¹ and R² is lower alkylsulfonyl, halo, cyano, nitro, or hydrogen and the other is lower alkylsulfonyl.
 169. The compound of claim 168, wherein said amide is3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide.170. The compound of claim 168, wherein said amide is3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide.171. The compound of claim 168, wherein said amide is2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.172. The compound of claim 168, wherein said amide is2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.173. The compound of claim 168, wherein said amide is3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide.174. The compound of claim 168, wherein said amide is2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.175. The compound of claim 168, wherein said amide is2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.176. The compound of claim 168, wherein said amide is2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.177. The compound of claim 150, wherein one of R¹ and R² isperfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen and theother is perfluoro-lower alkyl sulfonyl, or perfluro-lower alkyl. 178.The compound of claim 177, wherein said amide is3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide.179. The compound of claim 177, wherein said amide is3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide.180. The compound of claim 4 wherein R⁴ is a pyridine ringmono-substituted with one of said substituents.
 181. The compound ofclaim 180, wherein said substituent is cyano.
 182. The compound of claim181, wherein one of R¹ or R² is halo or perfluoro lower alkyl and theother is halo or lower alkyl thio.
 183. The compound of claim 182,wherein said amide isN-(5-cyano-pyridin-2-yl)-3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionamide.184. The compound of claim 182, wherein said amide isN-(5-cyano-pyridin-2-yl)-3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamide.185. The compound of claim 182, wherein said amide isN-(5-cyano-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)-propionamide.186. The compound of claim 180, wherein said substitutent is—(CH₂)_(n)—C(O)—OR⁷ wherein n and R⁷ are as above.
 187. The compound ofclaim 186, wherein R¹ and R² are each independently halo.
 188. Thecompound of claim 187, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-propionamide.189. The compound of claim 187, wherein said amide is6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinicacid methyl ester.
 190. The compound of claim 187, wherein said amide is6-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-nicotinic acid.191. The compound of claim 187, wherein said amide is6-[3-cyclopentyl-2-2(R)-(3,4-dichlorophenyl)-propionylamino]-nicotinicacid.
 192. The compound of claim 186, wherein one of R¹ and R² ishydrogen or halo and the other is halo, amino, cyano, nitro orperfluoro-lower alkyl.
 193. The compound of claim 192, wherein saidamide is 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinicacid.
 194. The compound of claim 192, wherein said amide is6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester.
 195. The compound of claim 192, wherein said amide is6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester.
 196. The compound of claim 192, wherein said amide is6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acidmethyl ester.
 197. The compound of claim 192, wherein said amide is6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester.
 198. The compound of claim 192, wherein said amide is6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid.199. The compound of claim 192, wherein said amide is6-[2-(4-cyano-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acidmethyl ester.
 200. The compound of claim 192, wherein said amide is6-[3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionylamino]-nicotinicacid methyl ester.
 201. The compound of claim 192, wherein said amide is6-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-nicotinicacid methyl ester.
 202. The compound of claim 186, wherein one of R¹ andR² is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogenand the other is perfluoro-lower alkyl sulfonyl or lower alkyl sulfonyl.203. The compound of claim 202, wherein said amide is6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinicacid methyl ester.
 204. The compound of claim 202, wherein said amide is6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinicacid.
 205. The compound of claim 202, wherein said amide is6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinicacid methyl ester.
 206. The compound of claim 180, wherein saidsubstituent is —(CH₂)_(n)—OR⁷ wherein n and R⁷ are as above.
 207. Thecompound of claim 206, wherein one of R¹ and R² are halo and the otheris hydrogen or halo.
 208. The compound of claim 207, wherein said amideis3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)propionamide.
 209. The compound of claim 207, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide.210. The compound of claim 207, wherein said amide is2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide.211. The compound of claim 207, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide.212. The compound of claim 206, wherein one of R¹ and R² is lower alkylsulfonyl or hydrogen and the other is lower alkyl sulfonyl.
 213. Thecompound of claim 212, wherein said amide is3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide.214. The compound of claim 180, wherein said substituent is halo orperfluoro-lower alkyl.
 215. The compound of claim 214, wherein one of R¹and R² is halo or perfluoro-lower alkyl and the other is halo, nitro,lower alkyl sulfonyl, or lower alkyl thio.
 216. The compound of claim215, wherein said amide isN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamide.217. The compound of claim 215, wherein said amide isN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide.218. The compound of claim 215, wherein said amide isN-(5-bromo-pyridin-2-yl)-2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide219. The compound of claim 215, wherein said amide isN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionamide.220. The compound of claim 214, wherein one of R¹ and R² is halo orhydrogen and the other is halo.
 221. The compound of claim 220, whereinsaid amide isN-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide.222. The compound of claim 220, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-brompyridin)-2-yl-propionamide.223. The compound of claim 220, wherein said amide is3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide.224. The compound of claim 220, wherein said amide isN-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionamide.225. The compound of claim 220, wherein said amide isN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide.226. The compound of claim 214, wherein one of R¹ and R² is halo, nitroor hydrogen and the other is perfluoro-lower alkyl sulfonyl or loweralkyl sulfonyl.
 227. The compound of claim 226, wherein said amide isN-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide.228. The compound of claim 226, wherein said amide isN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide.229. The compound of claim 226, wherein said amide isN-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide.230. The compound of claim 226, wherein said amide is2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-propionamide.231. The compound of claim 226, wherein said amide isN-(5-bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide.232. The compound of claim 226, wherein said amide is2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide.233. The compound of claim 226, wherein said amide isN-(5-chloro-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide.234. The compound of claim 226, wherein said amide isN-(5-bromo-pyridin-2-yl)2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide.235. The compound of claim 180, wherein said substituent is nitro. 236.The compound of claim 235, wherein one of R¹ and R² is halo orperfluoro-lower alkyl and the other is halo or lower alkyl thio. 237.The compound of claim 236, wherein said amide is3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide.238. The compound of claim 236, wherein said amide is3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide.239. The compound of claim 236, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-nitropyridin)-2-yl-propionamide.240. The compound of claim 180, wherein said substituent is lower alkyl.241. The compound of claim 240, wherein one of R¹ and R² is halo and theother is lower alkyl sulfonyl.
 242. The compound of claim 241, whereinsaid amide is2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-propionamide.243. The compound of claim 240, wherein one of R¹ and R² is halo orhydrogen and the other of said R¹ and R² is halo, perfluoro-lower alkyl,lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl.
 244. Thecompound of claim 243, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-methylpyridin)-2-yl-propionamide.245. The compound of claim 243, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4-methylpyridin)-2-yl-propionamide.246. The compound of claim 243, wherein said amide is3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-methylpyridin)-2-yl-propionamide.247. The compound of claim 243, wherein said amide is3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide.248. The compound of claim 243, wherein said amide is3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide.249. The compound of claim 243, wherein said amide is3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide.250. The compound of claim 180, wherein said substituent is—(CH₂)_(n)—C(O)—NH—R⁷ wherein n and R¹ are as above.
 251. The compoundof claim 250, wherein one of R¹ and R² is halo or hydrogen and the otherof said R¹ and R² is halo, or lower alkyl sulfonyl.
 252. The compound ofclaim 251, wherein said amide is6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide.253. The compound of claim 4 wherein R⁴ is unsubstituted imidazolyl.254. The compound of claim 253 wherein one of R¹ and R₂ is lower alkylsulfonyl and the other is nitro or perfluoro-lower alkyl.
 255. Thecompound of claim 254, wherein said amide is3-cyclopentyl-N-(1H-imidazol-2-yl)-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide.256. The compound of claim 254, wherein said amide is3-cyclopentyl-N-(1H-imidazol-2-yl)-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide.257. The compound of claim 253, wherein one of R¹ and R² is selectedfrom the group consisting of halo and hydrogen and the other of said R¹and R² is halo, or lower alkyl sulfonyl.
 258. The compound of claim 257,wherein said amide is2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-imidazol-2-yl)-propionamide.259. The compound of claim 257, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide.260. The compound of claim 4 wherein R⁴ is an isoxazolyl ring.
 261. Thecompound of claim 260, wherein said ring is substituted with a loweralkyl substituent.
 262. The compound of claim 261, wherein one of R¹ orR² is halo, nitro or perfluoro-lower alkyl, or lower alkyl sulfonyl andthe other of said R¹ or R² is hydrogen or halo.
 263. The compound ofclaim 262, wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionamide.264. The compound of claim 4 wherein R⁴ is unsubstituted oxazolyl. 265.The compound of claim 264, wherein one of R¹ or R² is halo, nitro orperfluoro-lower alkyl or lower alkyl sulfonyl and the other of said R¹or R² is hydrogen or halo.
 266. The compound of claim 265, wherein saidamide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide. 267.The compound of claim 4 wherein R⁴ is an unsubstituted thiadiazolylring.
 268. The compound of claim 267, wherein one of R¹ or R² is halo,nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and the other ofsaid R¹ and R² is hydrogen or halo.
 269. The compound of claim 268,wherein said amide is3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide.270. The compound of claim 1, wherein R³ is cyclohexyl.
 271. Thecompound of claim 270, wherein R⁴ is unsubstituted thiazolyl.
 272. Thecompound of claim 271, wherein one of R¹ and R² is halo, lower alkylsulfonyl, perfluoro-lower alkyl sulfonyl, perfluoro-lower alkyl, and theother of said R¹ and R² is halo, perfluoro-lower alkyl or hydrogen. 273.The compound of claim 272, wherein said amide is3-cyclohexyl-2-[4-methanesulfonyl-phenyl]-N-thiazol-2-yl-propionamide.274. The compound of claim 272, wherein said amide is3-cyclohexyl-2-[4-methanesulfonyl-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide.275. The compound of claim 1, wherein R³ is cycloheptyl.
 276. Thecompound of claim 275, wherein R⁴ is unsubstituted thiazolyl.
 277. Thecompound of claim 276, wherein one of R¹ and R² is halo, lower alkylsulfonyl, perfluoro-lower alkyl sulfonyl, perfluoro-lower alkyl, and theother of said R¹ and R² is halo, perfluoro-lower alkyl or hydrogen. 278.The compound of claim 277, wherein said amide is3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide.